Seed Fund Grants

MI4 Seed Fund Grants – Round 5

MI4 is pleased to award funding for five projects in the fifth round of the MI4 Seed Fund Grant program.

Please join us in congratulating the following MI4 researchers on their successful submissions!

MI4 Seed Fund Grant	Lead PIs
Reducing antibiotic abuse at the primary care level using locally adapted, digitally delivered, clinical decision support tool: a pilot, intervention study in India Antibiotic abuse is a major concern at the primary care level in low- and middle-income countries, and the COVID pandemic has aggravated this practice. WHO just published the AWaRe antibiotic book, which provides best practices in clinical assessment, diagnosis and treatment of various infections. But the WHO antibiotic book is unlikely to get scaled-up, unless it is adapted to the local context, translated into regional languages, and delivered effectively to primary care physicians via decision aids, enhanced by shared decision making. We propose to evaluate, using a before and after study, whether a locally adapted, digitally delivered, clinical decision support tool and training intervention can reduce antibiotic use among private primary care providers in Patna, India. Our study will rely on the standardized patient methodology that we have successfully used in many countries. Our findings will provide preliminary evidence on private providers’ antibiotic prescription practices, and effectiveness of a locally adapted, digitally delivered, decision tool and training intervention in shared decision making and reducing antibiotic use among private providers. Our results will inform antibiotic stewardship programs and will set the stage for a future randomized controlled trial. Such work will have great relevance in lower-income as well as high-income nations.	Samira Abbasgholizadeh Rahimi Madhukar Pai
Investigating the impact of impaired immune responses on viral diversity in humans and mice Large numbers of undiscovered viruses circulate in wild-life, some of which have the potential to cross into humans and cause disease, as did SARS-CoV-2, a coronavirus which likely originated from Chinese horseshoe bats. Most viruses will replicate poorly in humans, but some may gain a foothold, adapt and spread. What drives viral evolution after they jump from one species to another remains incompletely understood, but it is clear that the ensuing arms race between the immune response and the virus plays a key role. Thus, weak or impaired immune responses may facilitate the generation of viral variants through mutations in the viral sequence. Indeed, one feature of all vertebrates is that they share the ability to produce many different versions of one particular type of immune cell, the T cell, such that each T cell bears a unique T cell receptor. T cell receptor diversity has been thought to be critical precisely to limit viral mutations that allow them to escape immune responses. Here we will experimentally test this idea, investigating viral diversity and evolution in people with heart disease who have been documented to be more susceptible to infection, and in mice that have a reduced T cell repertoire.	Judith Mandl Abhinav Sharma
Targeting the gut microbiome to mitigate cholesterol-related diseases Excess amounts of blood cholesterol, particularly low-density lipoprotein (LDL) or “bad” cholesterol, are major risk factors for the development of cardiovascular disease (CVD) as well as Alzheimer’s disease (AD), the most common form of dementia in older adults. However, the underlying reasons for the development and progression of these vascular diseases remain to be determined. Over the last decade, a prominent role for the diverse community of microorganisms in the intestine, known as the gut microbiome, in the modulation of CVD and AD has emerged. Although the molecular pathways that originate from the gut microbiome to impact disease are only beginning to be understood, the ability of diverse bacterial species to metabolize dietary components, including cholesterol, is an emerging area of investigation. However, the ability of the gut microbiome to directly impact systemic cholesterol and LDL levels has not been shown. Here we propose to identify human gut microbiomes that are enriched for cholesterol breakdown and, using fecal transplantation approaches in mice, directly test the ability of these microbial communities to prevent high LDL levels and maintain a healthy heart and brain. Results from this seed grant project will set a foundation for identifying components of the human gut microbiome that can be used as a point of intervention for the prevention and/or treatment of CVD and AD-related pathologies.	Lisa Munter Irah King
Early life BCG vaccination shaping gut microbiome and subsequently host defense against tuberculosis Despite more than 100 years since the discovery of Mycobacterium tuberculosis (Mtb), this organism remains one of the most successful human pathogens. Approximately 2 million people die of TB annually and 8 to 10 million new cases of active tuberculosis occur each year. Bacillus Calmette–Guérin (BCG) is the only available vaccine against TB that provides protection in children but not adults. However, it is astonishing that the protective mechanism(s) of BCG in children, where it prevents the disseminated form of the disease is incompletely understood. Conventionally, it has been considered that BCG enhances host immunity against TB via T cell mediated immunity. However, there is little evidence to support this as the most dominant antigens of M. tuberculosis are missing in BCG and there is no direct link between BCG specific T cells and protection against TB. Unconventionally, there is a growing body of literature indicating that BCG can generate innate memory responses (termed trained immunity) providing protection against TB. Given the remarkable safety track record of BCG vaccination as well as the epidemiological studies supporting the efficacy of BCG vaccination against TB in children, in the current proposal, we aim to dissect the protective mechanism(s) of BCG in neonates as a roadmap for developing a novel vaccine against TB.	Corinne Maurice Maziar Divangahi
Erythrocyte Biphosphoglycerate Mutase (BPGM) as a novel Anti-Malarial Drug Target BPGM is an erythrocyte specific multi-functional enzyme responsible for the synthesis of 2,3- biphosphoglycerate (2,3-BPG), a key regulator of hemoglobin/oxygen interaction. It is also required for efficient glycolysis and energy (ATP) production in erythrocytes, via 2,3-BPG regulation of posphoglycerate mutase 1 (PGAM1). BPGM-deficient humans and mice show erythrocytosis, with low intra-erythrocytic 2,3-BPG and ATP levels. We recently discovered that BPGM deficiency protects mice against both blood-stage and severe cerebral malaria. Protection is linked to reduced replication and maturation of Plasmodium parasites in ATP-poor mutant erythrocytes. We wish to use two available BPGM small molecule inhibitors to test the novel hypothesis that BPGM may be an attractive therapeutic target for anti-malarial drug development. We will test the capacity of such compounds to a) inhibit BPGM-dependent ATP production in erythrocytes, and b) dampen replication of mouse and human Plasmodium parasites in erythrocytes in vitro, and in live animals in vivo. We will also investigate whether BPGM inhibitors may be active against parasites resistant to chloroquine, mefloquine or artemisinins. These studies may help address the critical global health threat of emerging drug resistance in malarial parasites.	Philippe Gros Momar Ndao

MI4 Seed Fund Grant

Lead PIs

Reducing antibiotic abuse at the primary care level using locally adapted, digitally delivered, clinical decision support tool: a pilot, intervention study in India

Antibiotic abuse is a major concern at the primary care level in low- and middle-income countries, and the COVID pandemic has aggravated this practice. WHO just published the AWaRe antibiotic book, which provides best practices in clinical assessment, diagnosis and treatment of various infections. But the WHO antibiotic book is unlikely to get scaled-up, unless it is adapted to the local context, translated into regional languages, and delivered effectively to primary care physicians via decision aids, enhanced by shared decision making. We propose to evaluate, using a before and after study, whether a locally adapted, digitally delivered, clinical decision support tool and training intervention can reduce antibiotic use among private primary care providers in Patna, India. Our study will rely on the standardized patient methodology that we have successfully used in many countries. Our findings will provide preliminary evidence on private providers’ antibiotic prescription practices, and effectiveness of a locally adapted, digitally delivered, decision tool and training intervention in shared decision making and reducing antibiotic use among private providers. Our results will inform antibiotic stewardship programs and will set the stage for a future randomized controlled trial. Such work will have great relevance in lower-income as well as high-income nations.

Samira Abbasgholizadeh Rahimi

Madhukar Pai

Investigating the impact of impaired immune responses on viral diversity in humans and mice

Large numbers of undiscovered viruses circulate in wild-life, some of which have the potential to cross into humans and cause disease, as did SARS-CoV-2, a coronavirus which likely originated from Chinese horseshoe bats. Most viruses will replicate poorly in humans, but some may gain a foothold, adapt and spread. What drives viral evolution after they jump from one species to another remains incompletely understood, but it is clear that the ensuing arms race between the immune response and the virus plays a key role. Thus, weak or impaired immune responses may facilitate the generation of viral variants through mutations in the viral sequence. Indeed, one feature of all vertebrates is that they share the ability to produce many different versions of one particular type of immune cell, the T cell, such that each T cell bears a unique T cell receptor. T cell receptor diversity has been thought to be critical precisely to limit viral mutations that allow them to escape immune responses. Here we will experimentally test this idea, investigating viral diversity and evolution in people with heart disease who have been documented to be more susceptible to infection, and in mice that have a reduced T cell repertoire.

Judith Mandl

Abhinav Sharma

Targeting the gut microbiome to mitigate cholesterol-related diseases

Excess amounts of blood cholesterol, particularly low-density lipoprotein (LDL) or “bad” cholesterol, are major risk factors for the development of cardiovascular disease (CVD) as well as Alzheimer’s disease (AD), the most common form of dementia in older adults. However, the underlying reasons for the development and progression of these vascular diseases remain to be determined. Over the last decade, a prominent role for the diverse community of microorganisms in the intestine, known as the gut microbiome, in the modulation of CVD and AD has emerged. Although the molecular pathways that originate from the gut microbiome to impact disease are only beginning to be understood, the ability of diverse bacterial species to metabolize dietary components, including cholesterol, is an emerging area of investigation. However, the ability of the gut microbiome to directly impact systemic cholesterol and LDL levels has not been shown. Here we propose to identify human gut microbiomes that are enriched for cholesterol breakdown and, using fecal transplantation approaches in mice, directly test the ability of these microbial communities to prevent high LDL levels and maintain a healthy heart and brain. Results from this seed grant project will set a foundation for identifying components of the human gut microbiome that can be used as a point of intervention for the prevention and/or treatment of CVD and AD-related pathologies.

Lisa Munter

Irah King

Early life BCG vaccination shaping gut microbiome and subsequently host defense against tuberculosis

Despite more than 100 years since the discovery of Mycobacterium tuberculosis (Mtb), this organism remains one of the most successful human pathogens. Approximately 2 million people die of TB annually and 8 to 10 million new cases of active tuberculosis occur each year. Bacillus Calmette–Guérin (BCG) is the only available vaccine against TB that provides protection in children but not adults. However, it is astonishing that the protective mechanism(s) of BCG in children, where it prevents the disseminated form of the disease is incompletely understood. Conventionally, it has been considered that BCG enhances host immunity against TB via T cell mediated immunity. However, there is little evidence to support this as the most dominant antigens of M. tuberculosis are missing in BCG and there is no direct link between BCG specific T cells and protection against TB. Unconventionally, there is a growing body of literature indicating that BCG can generate innate memory responses (termed trained immunity) providing protection against TB. Given the remarkable safety track record of BCG vaccination as well as the epidemiological studies supporting the efficacy of BCG vaccination against TB in children, in the current proposal, we aim to dissect the protective mechanism(s) of BCG in neonates as a roadmap for developing a novel vaccine against TB.

Corinne Maurice

Maziar Divangahi

Erythrocyte Biphosphoglycerate Mutase (BPGM) as a novel Anti-Malarial Drug Target

BPGM is an erythrocyte specific multi-functional enzyme responsible for the synthesis of 2,3- biphosphoglycerate (2,3-BPG), a key regulator of hemoglobin/oxygen interaction. It is also required for efficient glycolysis and energy (ATP) production in erythrocytes, via 2,3-BPG regulation of posphoglycerate mutase 1 (PGAM1). BPGM-deficient humans and mice show erythrocytosis, with low intra-erythrocytic 2,3-BPG and ATP levels. We recently discovered that BPGM deficiency protects mice against both blood-stage and severe cerebral malaria. Protection is linked to reduced replication and maturation of Plasmodium parasites in ATP-poor mutant erythrocytes. We wish to use two available BPGM small molecule inhibitors to test the novel hypothesis that BPGM may be an attractive therapeutic target for anti-malarial drug development. We will test the capacity of such compounds to a) inhibit BPGM-dependent ATP production in erythrocytes, and b) dampen replication of mouse and human Plasmodium parasites in erythrocytes in vitro, and in live animals in vivo. We will also investigate whether BPGM inhibitors may be active against parasites resistant to chloroquine, mefloquine or artemisinins. These studies may help address the critical global health threat of emerging drug resistance in malarial parasites.

Philippe Gros

Momar Ndao

MI4 Seed Fund Grants – Round 4

MI4 is pleased to award funding for five projects in the fourth round of the MI4 Seed Fund Grant program.

Please join us in congratulating the following MI4 researchers on their successful submissions!

MI4 Seed Fund Grant	Lead PIs
A multidisciplinary approach to tackle multidrug resistant - tuberculosis (MDR-TB) Despite the availability of antibiotic drug treatment for more than 50 years, 1.5 million people globally still die from tuberculosis (TB) each year. In particular, the spread of multidrug resistant (MDR) forms of Mycobacterium tuberculosis (Mtb) is one of the major obstacles that is fueling the ongoing TB epidemic and there are 500,000 new MDR-TB cases recorded worldwide every year! Acquiring the genetic mutations that lead to antibiotic resistance places a substantial “fitness” burden on the M. tuberculosis cell. As such, the goal for the current proposal is to combine a bacterial mutagenesis screen with large-scale computational genomics to identify critical weaknesses that are specific to MDR-TB bacteria. In turn, the results of our work will pave the way for the development of novel “resistance-breaking” agents that can be added to our current drug-treatment regimens in order to restore antibiotic sensitivity. Overall, our program affords a unique opportunity to extend the life and usability of the currently available first-line TB drugs - including Rifampicin and Isoniazid - that have, in many cases, been rendered practically useless in the face of drug resistant forms of TB.	Michael Reed Jesse Shapiro
Discovering Novel Antimicrobials from the Canadian High Arctic We propose a unique approach to antimicrobial discovery. As resistance to the currently available arsenal of antimicrobial therapy increases, new antimicrobials with novel mechanisms of action are urgently needed. Problems plaguing early drug discovery initiatives include the re-discovery of known antimicrobials and the fact that the vast majority of environmental bacteria are not culturable under standard laboratory conditions. We propose to overcome these limitations by mining the microbiome of an extremely understudied environment, the Canadian high Arctic, and by employing innovative bacterial culturing methods. Our team brings together experts in the collection and cultivation of polar microorganisms, host-pathogen interactions, antimicrobial resistance, chemistry and drug discovery. Together we propose to bring novel antimicrobials from the Arctic to the laboratory. We have identified several extracts with antibacterial and/or antifungal activity and developed a bioactivity-guided fractionation protocol to isolate the bioactive molecules. At the end of the MI4 seed funding project, we expect to have determined the chemical structure of 1-5 new antimicrobials and determined whether they act via a new mechanism of action. These outcomes will provide essential preliminary data to secure external funding with the long-term goal of developing novel therapeutics to aid in the fight against antimicrobial resistance.	Dao Nguyen Karine Auclair
Point-of-care Rapid Test for Rogue Anti-Cytokine Auto-Antibodies in COVID-19 Patients Antibodies are well-known for protecting the body against infections. Some individuals, however, produce auto-antibodies (AAbs) that attack components of their own body, rather than microbes. Some AAbs attack certain hormones of the immune system (called "cytokines"), causing otherwise-healthy individuals to be susceptible to infections. This has been shown in COVID-19: AAbs to the cytokine, "type I interferon" (IFN), are found in >10% of patients with severe COVID, but especially in 20% of elderly patients with life-threatening COVID. Because these AAbs are present in the blood at the time of SARS-CoV-2 infection, and they determine the patient's prognosis, identifying those with AAbs to IFN – as early as possible following infection – could guide and accelerate acute management and help improve outcomes. Unfortunately, current tests for AAbs to IFN are onerous, slow and done in batches at the MUHC (the test is done when there are sufficient numbers of samples). The development of a test that is faster, just as accurate, and that can be done on single samples, in a portable format and instrumentation-free, is much needed. In this study, we combine the immunological experience of the Vinh lab with the bioengineering expertise of the Juncker lab to develop a prototype of such a test, evaluate and validate it in clinical settings. Upon completion of the project, we will further develop the prototype with our industrial collaborator Sensoreal Inc., integrating easy-to-use liquid reagent storage and delivery mechanisms, production by mass manufacturing method, long-term storage, towards realizing a point-of-care test that would positively impact current clinical practice.	Donald Vinh David Juncker
The impact of viral infection on the initiation and development of systemic lupus erythematosus (SLE) Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting an estimated 4.4 in 100,000 Canadians that can result in life-long suffering and premature death. Individuals with SLE develop an immune response against their own cells, but it is unclear why this happens. While the origin of SLE eludes us, it is clear that both genetic predisposition and environmental triggers are important. In particular, viral infections have been associated with SLE, causing disease “flares” (more severe disease). However, studies in SLE patients are limited to clinical associations, and have not shown directly that viral infection affects SLE. Dr. Rauch’s laboratory has developed a murine model of SLE, in which she can cause SLE to develop in a normally healthy mouse. Dr. Mandl’s laboratory uses a model of acute (short-term) viral infection with a virus called LCMV. Here, we propose to use LCMV infection in mouse models of SLE, and ask whether viral infection can initiate SLE in a healthy mouse or make it worse in a mouse that already has SLE. These studies will provide us with an understanding of how and when viral infection affects SLE, and has the potential to impact both knowledge about SLE and patient care.	Joyce Rauch Judith Mandl
Targeting soluble CD109 in mesenchymal stem cell (MSC) secretome for the treatment of fibrosis in scleroderma Scleroderma or systemic sclerosis (SSc) is a chronic connective tissue disease characterized by defective immune system function, blood vessel damage and fibrosis of the skin and internal organs. Fibrosis is a prominent feature of SSc and involves excessive production of extracellular matrix proteins leading to disruption of tissue structure and eventually organ failure. Administration of multipotent mesenchymal stromal cells (MSCs) has emerged as a promising therapeutic treatment of SSc, and it has been suggested that factors secreted by MSCs mediates the beneficial anti-fibrotic effects of MSCs. We have previously shown that soluble CD109 is a potent endogenous anti-fibrotic molecule and that MSCs releases substantial amounts of this protein. Our main goal is to determine whether soluble CD109 released from MSCs can reduce fibrosis in SSc skin cells and in animal models of SSc. Results from these studies may lead to the development of a novel therapeutic strategy for the treatment of SSc.	Anie Philip Dieter Reinhardt

MI4 Seed Fund Grant

Lead PIs

A multidisciplinary approach to tackle multidrug resistant - tuberculosis (MDR-TB)

Despite the availability of antibiotic drug treatment for more than 50 years, 1.5 million people globally still die from tuberculosis (TB) each year. In particular, the spread of multidrug resistant (MDR) forms of Mycobacterium tuberculosis (Mtb) is one of the major obstacles that is fueling the ongoing TB epidemic and there are 500,000 new MDR-TB cases recorded worldwide every year! Acquiring the genetic mutations that lead to antibiotic resistance places a substantial “fitness” burden on the M. tuberculosis cell. As such, the goal for the current proposal is to combine a bacterial mutagenesis screen with large-scale computational genomics to identify critical weaknesses that are specific to MDR-TB bacteria. In turn, the results of our work will pave the way for the development of novel “resistance-breaking” agents that can be added to our current drug-treatment regimens in order to restore antibiotic sensitivity. Overall, our program affords a unique opportunity to extend the life and usability of the currently available first-line TB drugs - including Rifampicin and Isoniazid - that have, in many cases, been rendered practically useless in the face of drug resistant forms of TB.

Michael Reed

Jesse Shapiro

Discovering Novel Antimicrobials from the Canadian High Arctic

We propose a unique approach to antimicrobial discovery. As resistance to the currently available arsenal of antimicrobial therapy increases, new antimicrobials with novel mechanisms of action are urgently needed. Problems plaguing early drug discovery initiatives include the re-discovery of known antimicrobials and the fact that the vast majority of environmental bacteria are not culturable under standard laboratory conditions. We propose to overcome these limitations by mining the microbiome of an extremely understudied environment, the Canadian high Arctic, and by employing innovative bacterial culturing methods. Our team brings together experts in the collection and cultivation of polar microorganisms, host-pathogen interactions, antimicrobial resistance, chemistry and drug discovery. Together we propose to bring novel antimicrobials from the Arctic to the laboratory. We have identified several extracts with antibacterial and/or antifungal activity and developed a bioactivity-guided fractionation protocol to isolate the bioactive molecules. At the end of the MI4 seed funding project, we expect to have determined the chemical structure of 1-5 new antimicrobials and determined whether they act via a new mechanism of action. These outcomes will provide essential preliminary data to secure external funding with the long-term goal of developing novel therapeutics to aid in the fight against antimicrobial resistance.

Dao Nguyen

Karine Auclair

Point-of-care Rapid Test for Rogue Anti-Cytokine Auto-Antibodies in COVID-19 Patients

Antibodies are well-known for protecting the body against infections. Some individuals, however, produce auto-antibodies (AAbs) that attack components of their own body, rather than microbes. Some AAbs attack certain hormones of the immune system (called "cytokines"), causing otherwise-healthy individuals to be susceptible to infections. This has been shown in COVID-19: AAbs to the cytokine, "type I interferon" (IFN), are found in >10% of patients with severe COVID, but especially in 20% of elderly patients with life-threatening COVID. Because these AAbs are present in the blood at the time of SARS-CoV-2 infection, and they determine the patient's prognosis, identifying those with AAbs to IFN – as early as possible following infection – could guide and accelerate acute management and help improve outcomes. Unfortunately, current tests for AAbs to IFN are onerous, slow and done in batches at the MUHC (the test is done when there are sufficient numbers of samples). The development of a test that is faster, just as accurate, and that can be done on single samples, in a portable format and instrumentation-free, is much needed. In this study, we combine the immunological experience of the Vinh lab with the bioengineering expertise of the Juncker lab to develop a prototype of such a test, evaluate and validate it in clinical settings. Upon completion of the project, we will further develop the prototype with our industrial collaborator Sensoreal Inc., integrating easy-to-use liquid reagent storage and delivery mechanisms, production by mass manufacturing method, long-term storage, towards realizing a point-of-care test that would positively impact current clinical practice.

Donald Vinh

David Juncker

The impact of viral infection on the initiation and development of systemic lupus erythematosus (SLE)

Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting an estimated 4.4 in 100,000 Canadians that can result in life-long suffering and premature death. Individuals with SLE develop an immune response against their own cells, but it is unclear why this happens. While the origin of SLE eludes us, it is clear that both genetic predisposition and environmental triggers are important. In particular, viral infections have been associated with SLE, causing disease “flares” (more severe disease). However, studies in SLE patients are limited to clinical associations, and have not shown directly that viral infection affects SLE. Dr. Rauch’s laboratory has developed a murine model of SLE, in which she can cause SLE to develop in a normally healthy mouse. Dr. Mandl’s laboratory uses a model of acute (short-term) viral infection with a virus called LCMV. Here, we propose to use LCMV infection in mouse models of SLE, and ask whether viral infection can initiate SLE in a healthy mouse or make it worse in a mouse that already has SLE. These studies will provide us with an understanding of how and when viral infection affects SLE, and has the potential to impact both knowledge about SLE and patient care.

Joyce Rauch

Judith Mandl

Targeting soluble CD109 in mesenchymal stem cell (MSC) secretome for the treatment of fibrosis in scleroderma

Scleroderma or systemic sclerosis (SSc) is a chronic connective tissue disease characterized by defective immune system function, blood vessel damage and fibrosis of the skin and internal organs. Fibrosis is a prominent feature of SSc and involves excessive production of extracellular matrix proteins leading to disruption of tissue structure and eventually organ failure. Administration of multipotent mesenchymal stromal cells (MSCs) has emerged as a promising therapeutic treatment of SSc, and it has been suggested that factors secreted by MSCs mediates the beneficial anti-fibrotic effects of MSCs. We have previously shown that soluble CD109 is a potent endogenous anti-fibrotic molecule and that MSCs releases substantial amounts of this protein. Our main goal is to determine whether soluble CD109 released from MSCs can reduce fibrosis in SSc skin cells and in animal models of SSc. Results from these studies may lead to the development of a novel therapeutic strategy for the treatment of SSc.

Anie Philip

Dieter Reinhardt

Ludmer - MI4 Collaborative Seed Fund Grant

MI4 and the Ludmer Centre are pleased to announce the results of the Ludmer-MI4 Collaborative Seed Fund Grant Competition! This grant aimed at supporting a new health research project focusing on the role of infection, immunity and/or the microbiome in the development, prevention or treatment of mental health disorders.

Please join us in congratulating Dr. Patricia Silveira and Dr. Nicolas Cermakian on their successful submission!

Seed Fund Grant Title	Lead PIs
Maternal immune activation and circadian disruption as risk factors for mental disorders – using transcriptomics to identify individual differences in susceptibility Schizophrenia is a severe neurodevelopmental disorder with lifetime prevalence ~1%. The occurrence of neurodevelopmental disorders such as schizophrenia and autism spectrum disorders rely on a combination of risk factors, including genetic variants and environmental factors. Exposure to prenatal infections is associated with increased risk for neurodevelopmental disorders. For example, influenza infection during pregnancy first trimester leads to a 7-fold risk of the offspring to develop schizophrenia. Up to 80% of patients with schizophrenia show disrupted sleep and circadian rhythms. This led us to propose circadian disturbances as a possible risk factor for schizophrenia, which our recent findings in mice support. This is important because circadian alterations are common in our modern-day societies (e.g. in shift workers, but also, for a large proportion of the population, with modern lifestyle involving irregular schedules of activity, light exposure and meal timing). Here we plan to identify mechanisms underlying this interaction between an immune-related risk factor (maternal infection) with a new environmental risk factor (circadian disruption). We will study the cellular and molecular bases for this interaction, by looking at the impact of the risk factors on gene expression at the cellular level in mouse brains. Furthermore, to underscore the translational potential of this research, we will use gene expression data to develop a new polygenic score as a tool to detect individual differences in susceptibility to these schizophrenia risk factors in human populations. This work will allow designing novel strategies, taking circadian rhythms into consideration, to prevent schizophrenia and other psychiatric conditions.	Dr. Patricia Silveira Dr. Nicolas Cermakian

Seed Fund Grant Title

Lead PIs

Maternal immune activation and circadian disruption as risk factors for mental disorders – using transcriptomics to identify individual differences in susceptibility

Schizophrenia is a severe neurodevelopmental disorder with lifetime prevalence ~1%. The occurrence of neurodevelopmental disorders such as schizophrenia and autism spectrum disorders rely on a combination of risk factors, including genetic variants and environmental factors. Exposure to prenatal infections is associated with increased risk for neurodevelopmental disorders. For example, influenza infection during pregnancy first trimester leads to a 7-fold risk of the offspring to develop schizophrenia. Up to 80% of patients with schizophrenia show disrupted sleep and circadian rhythms. This led us to propose circadian disturbances as a possible risk factor for schizophrenia, which our recent findings in mice support. This is important because circadian alterations are common in our modern-day societies (e.g. in shift workers, but also, for a large proportion of the population, with modern lifestyle involving irregular schedules of activity, light exposure and meal timing). Here we plan to identify mechanisms underlying this interaction between an immune-related risk factor (maternal infection) with a new environmental risk factor (circadian disruption). We will study the cellular and molecular bases for this interaction, by looking at the impact of the risk factors on gene expression at the cellular level in mouse brains. Furthermore, to underscore the translational potential of this research, we will use gene expression data to develop a new polygenic score as a tool to detect individual differences in susceptibility to these schizophrenia risk factors in human populations. This work will allow designing novel strategies, taking circadian rhythms into consideration, to prevent schizophrenia and other psychiatric conditions.

Dr. Patricia Silveira

Dr. Nicolas Cermakian

MRM-MI4 Collaborative Seed Fund Grant

MI4 and the McGill Regenerative Medicine (MRM) Network are pleased to announce the results of the MRM-MI4 Collaborative Seed Fund Grant Competition! This grant aimed at supporting a new health research project focusing on stem cell or regenerative medicine within the domains of either infection or immunity.

Congratulations to Dr. Alex Gregorieff!

Seed Fund Grant Title	Lead PI
Creation of a patient-derived enteroid biobank to study the role of intestinal stemcells in inflammatory bowel disease. Recent decades have seen an enormous rise in the incidence of inflammatory bowel diseases (IBD) in Canada, with over 270,000 Canadians now living with IBD and costs to the healthcare sector estimated at over 1.28 billion dollars 1. IBD, which includes ulcerative colitis (UC) and Crohn’s disease (CD) are the consequence of tissue-destructive immune responses triggered by host microbiota or other environmental factors. Therapies aimed at dampening inflammatory signals have significantly improved the quality of life of IBD patients. However, it is now well recognized that besides immunosuppression, long-term remission in IBD is highly dependent on the ability of the intestinal mucosa to heal ulcerations incurred during inflammation 2–4. A critical driver of mucosal healing is the regenerative capacity of the gut epithelium, a polarized cell layer that coordinates nutrient digestion, barrier formation and immune defense strategies. New findings from our lab have revealed how distinct populations of intestinal stem cells and their unique gene products govern repair of the gut epithelium. To further dissect the relevance of these findings in the context of human IBD our proposal aims to: 1) establish and functionally characterize enteroids or ‘mini guts’ obtained from biopsies of IBD patients enrolled in the recently launched MUHC IBD biobank; 2) harness this resource to uncover epithelial-intrinsic genetic pathways implicated in human IBD. Overall, our strategy will develop stem cell-based organoid technologies to deconvolve the complex tissue repair mechanisms and cellular interactions that dictate the course of IBD.	Alex Gregorieff

Seed Fund Grant Title

Lead PI

Creation of a patient-derived enteroid biobank to study the role of intestinal stemcells in inflammatory bowel disease.

Recent decades have seen an enormous rise in the incidence of inflammatory bowel diseases (IBD) in Canada, with over 270,000 Canadians now living with IBD and costs to the healthcare sector estimated at over 1.28 billion dollars 1. IBD, which includes ulcerative colitis (UC) and Crohn’s disease (CD) are the consequence of tissue-destructive immune responses triggered by host microbiota or other environmental factors. Therapies aimed at dampening inflammatory signals have significantly improved the quality of life of IBD patients. However, it is now well recognized that besides immunosuppression, long-term remission in IBD is highly dependent on the ability of the intestinal mucosa to heal ulcerations incurred during inflammation 2–4. A critical driver of mucosal healing is the regenerative capacity of the gut epithelium, a polarized cell layer that coordinates nutrient digestion, barrier formation and immune defense strategies. New findings from our lab have revealed how distinct populations of intestinal stem cells and their unique gene products govern repair of the gut epithelium. To further dissect the relevance of these findings in the context of human IBD our proposal aims to: 1) establish and functionally characterize enteroids or ‘mini guts’ obtained from biopsies of IBD patients enrolled in the recently launched MUHC IBD biobank; 2) harness this resource to uncover epithelial-intrinsic genetic pathways implicated in human IBD. Overall, our strategy will develop stem cell-based organoid technologies to deconvolve the complex tissue repair mechanisms and cellular interactions that dictate the course of IBD.

Alex Gregorieff

MI4 Seed Fund Grants - Round 3

MI4 is pleased to award funding for six projects in Round 3 of the MI4 Seed Fund Grant program. MI4 would like to acknowledge that support for this program has been provided by the Montreal Neurological Institute, The Montreal General Hospital Foundation and the Doggone Foundation donation to McGill University.

Please join us in congratulating the following MI4 researchers on their successful submissions!

MI4 Seed Fund Grant	Lead PIs
Biomarkers associated with infections in Canadians 45-85 years of age with and without diabetes: analysis of metabolomic and clinical data from the Canadian Longitudinal Study on Aging Diabetes affects a large number of middle-age and older Canadians. Infections, in particular pneumonia, influenza and urinary tract infections occur frequently in this age group and more so among those with diabetes (where they may also be more severe and even fatal). Vaccination protects against flu and some pneumonias, but many individuals with diabetes do not get vaccines despite recommendations. Also, some medications used to treat diabetes may increase the risk of urine infections and should be avoided in those at high risk. It is therefore important to elucidate factors that may help identify those at high risk of infections to better inform preventive measures and therapies. While previous studies have looked at the contribution of unhealthy lifestyle habits, low socioeconomic status and other health issues to the risk of infections in those with diabetes; no study has searched for metabolic biomarkers (compounds found in the blood or urine) that could identify those people with diabetes at most risk. We will address this knowledge gap using data from a large national representative group, the Canadian Longitudinal Study on Aging. Biomarkers, in addition to lifestyle and clinical factors identified in our study may further inform medication prescription and preventive measures.	Elham Rahme Robert Sladek
MENELIC-1 - Impact of mobile clinical decision support tool on prescription behaviour and patient outcomes in low-resource settings: A pilot trial of self-stewardship in Ethiopia Antimicrobial Resistance is a major threat for low- and middle-income countries. Without access to quality laboratories, healthcare workers are forced to operate with a blindfold, prescribing antibiotics indiscriminately - which further fuels the crisis in the very settings that can least afford it. We plan to assess the impact of a bundle of interventions consisting of scalable and sustainable laboratory support with an electronic decision support tool, on physician’s prescription behaviour.	Makeda Semret Nicole Basta
A colorimetric nanosurface fluidic platform for rapid phenotypic antibiotic susceptibility testing Antibiotic resistant bacteria are responsible for 700,000 deaths annually, a figure that is projected to rise to 10 million deaths per year by 2050 if no action is taken to halt this global threat. The overuse of antibiotics and the prescription of antibiotics to which bacteria are not susceptible, contribute to the rise of antibiotic resistance. This proposal brings together a bioengineer, a microbiologist and a clinical scientist to develop an ultrasensitive colorimetric fluidic assay for rapid phenotypic antibiotic susceptibility testing (AST), with versatile functionality for a broad range of pathogenic bacteria and the possibility for direct testing of human samples. The proposed diagnostic platform is based on a novel plasmonic nanostructure that provides an ultrasensitive optical readout during the conversion of resazurin to resorufin − an indicator for bacterial viability and growth during antibiotic exposure. The color-sensitive platform will be integrated with a fluidic sample delivery, containing parallel fluidic compartments to provide a portable, automated and multiplex test platform. We propose a modular plan which includes device fabrication and validation of the diagnostic platform. We will first develop our unique colorimetric fluid assay by fabricating a color-sensitive nanostructured platform integrated with a fluidic sample delivery. We will then validate the platform with a panel of key human pathogens displaying different drug susceptibility profiles and determine the minimum inhibitory concentration (MIC) of antibiotics, the sensitivity of the assay and the functionality of the assay in human body fluids. Finally, we will test the platform in clinical specimens from patients with suspected bacteremia at different stages of sample processing and compare the results with standard AST for microbial identification and susceptibility testing. It is anticipated that the proposed approach reduces the turnaround time of the AST to less than 1 hour compared to 3-4 days using conventional AST methods. The proposed project advances our knowledge of developing new, rapid and low-cost diagnostic methods ($5 per test) based on color sensing materials and will generate innovations and secure commercialization. The potential to reduce the time-to-result for phenotypic AST at a low-cost would have significant economic impact on the Canadian health system.	Sara Mahshid Dao Nguyen
At the heart of the matter - Speckle tracking echocardiography in lupus mothers and their offspring Women with systemic lupus erythematosus (SLE) have a high risk of placentamediated complications, which can lead to substantial cardiac morbidities in affected women and their offspring. In addition, maternal autoantibodies, which are actively transferred across the placenta during pregnancy, can affect the cardiovascular health of SLE offspring. Hydroxychloroquine (HCQ) is effective in preventing adverse pregnancy outcomes in SLE and might be beneficial in preventing fetal cardiovascular damage mediated by maternal autoantibodies. However, there are concerns that HCQ might cause maternal and neonatal cardiac toxicity. A novel imaging technique (i.e. speckle tracking echocardiography), which allows early identification of cardiac dysfunction, has proven superior to any other in assessing cardiac function in mothers and neonates experiencing placenta-mediated complications and in identifying drug cardiotoxicity. Yet, there has been no study using speckle tracking echocardiography to evaluate the cardiovascular health of pregnant SLE women and their offspring, as well as the potential adverse cardiac effect of HCQ. Moreover, due to unavailability of assays, HCQ dosing in SLE is generally done blindly, without checking drug levels. To fill these key knowledge gaps, we aim to: 1) assess the impact of placenta-mediated complications on maternal and neonatal cardiac function, 2) evaluate if HCQ exposure (as measured by whole-blood levels) is associated with maternal and neonatal outcomes including cardiac toxicity, and 3) determine the effect of maternal autoantibodies on neonatal cardiac function. Ultimately, our proposal will help optimize reproductive and cardiovascular outcomes in lupus women and their offspring.	Evelyne Vinet Lawrence Rudski
MI4 - MNI COLLABORATIVE SEED FUND GRANT	LEAD PIs
Inflammation-mediated white matter injury in pediatric encephalopathies Brain tissue destruction in newborns/young children, termed infantile hypoxic encephalopathy (IHE), often occurs consequent to systemic infectious and metabolic disorders and results in permanent neurologic sequela (cerebral palsy). A pathologic hallmark is injury to oligodendrocytes (OLs) – the cell type that produces myelin processes that wrap nerve fibers, allowing efficient electrical conduction. Such injury reflects the combined effects of inflammation and lack of oxygen/nutrients at injury sites. Recovery requires tissue repair by progenitor cells (termed OPCs) that can produce new OLs/myelin. Our aims are to: 1) perform functional studies on OL lineage cells derived from human surgically resected brain samples to determine their vulnerability to immune mediators (effector cytokines, glutamate) and metabolic stress (low glucose) as a function of donor age and cell differentiation stage. Concurrent bioinformatics analyses of bulk RNA sequenced cells will be used to identify contributing molecular mechanisms. 2) show that molecular signatures of injured OL lineage cells (defined by our in vitro studies) are represented in situ. We will use tissue sections from cases of IHE and controls for this analysis. Our results will direct the search for therapies that can protect OL lineage cells from injury and promote repair.	Jack Antel Myriam Srour
MI4 - MGH COLLABORATIVE SEED FUND GRANT	LEAD PIs
A Rabbit Prosthetic Joint Infection Model for Evaluation of Nano-Layered Antimicrobial Surface Coatings Infection following joint replacement surgery is increasing in incidence and is a devastating complication. Only a small quantity of bacteria introduced inadvertently during surgery can inoculate the surgical wound and implants, leading to infection. Bacteria quickly attach themselves to the implant surfaces and can evade the human immune system by growing in a protective slime layer called biofilm. Once infection ensues, the joint becomes painful and the patient inevitably requires multiple surgeries to clean or remove the implants. Consequently, infection is a serious complication that leads to a poor outcome. Antimicrobial surface coatings are a promising strategy to help prevent prosthetic joint infections. In particular, silver has well-known antimicrobial properties and has already been used to coat selective medical devices. Unfortunately, successful inhibition of bacteria by the silver on orthopedic implants has been tempered by the body’s local inflammatory reaction to silver which inhibits bone from growing into the implants, leading to failure. The proposed research explores a special fabrication technique using nanoparticles to construct a titanium dioxide coating that can minimize the undesired local tissue inflammation while maintaining the antimicrobial properties. Various configurations of this layering technology will be tested in a rabbit model to demonstrate proof of concept.	Adam Hart Maryam Tabrizian

MI4 Seed Fund Grant

Lead PIs

Biomarkers associated with infections in Canadians 45-85 years of age with and without diabetes: analysis of metabolomic and clinical data from the Canadian Longitudinal Study on Aging

Diabetes affects a large number of middle-age and older Canadians. Infections, in particular pneumonia, influenza and urinary tract infections occur frequently in this age group and more so among those with diabetes (where they may also be more severe and even fatal). Vaccination protects against flu and some pneumonias, but many individuals with diabetes do not get vaccines despite recommendations. Also, some medications used to treat diabetes may increase the risk of urine infections and should be avoided in those at high risk. It is therefore important to elucidate factors that may help identify those at high risk of infections to better inform preventive measures and therapies. While previous studies have looked at the contribution of unhealthy lifestyle habits, low socioeconomic status and other health issues to the risk of infections in those with diabetes; no study has searched for metabolic biomarkers (compounds found in the blood or urine) that could identify those people with diabetes at most risk. We will address this knowledge gap using data from a large national representative group, the Canadian Longitudinal Study on Aging. Biomarkers, in addition to lifestyle and clinical factors identified in our study may further inform medication prescription and preventive measures.

Elham Rahme

Robert Sladek

MENELIC-1 - Impact of mobile clinical decision support tool on prescription behaviour and patient outcomes in low-resource settings: A pilot trial of self-stewardship in Ethiopia

Antimicrobial Resistance is a major threat for low- and middle-income countries. Without access to quality laboratories, healthcare workers are forced to operate with a blindfold, prescribing antibiotics indiscriminately - which further fuels the crisis in the very settings that can least afford it. We plan to assess the impact of a bundle of interventions consisting of scalable and sustainable laboratory support with an electronic decision support tool, on physician’s prescription behaviour.

Makeda Semret

Nicole Basta

A colorimetric nanosurface fluidic platform for rapid phenotypic antibiotic susceptibility testing

Antibiotic resistant bacteria are responsible for 700,000 deaths annually, a figure that is projected to rise to 10 million deaths per year by 2050 if no action is taken to halt this global threat. The overuse of antibiotics and the prescription of antibiotics to which bacteria are not susceptible, contribute to the rise of antibiotic resistance. This proposal brings together a bioengineer, a microbiologist and a clinical scientist to develop an ultrasensitive colorimetric fluidic assay for rapid phenotypic antibiotic susceptibility testing (AST), with versatile functionality for a broad range of pathogenic bacteria and the possibility for direct testing of human samples. The proposed diagnostic platform is based on a novel plasmonic nanostructure that provides an ultrasensitive optical readout during the conversion of resazurin to resorufin − an indicator for bacterial viability and growth during antibiotic exposure. The color-sensitive platform will be integrated with a fluidic sample delivery, containing parallel fluidic compartments to provide a portable, automated and multiplex test platform. We propose a modular plan which includes device fabrication and validation of the diagnostic platform. We will first develop our unique colorimetric fluid assay by fabricating a color-sensitive nanostructured platform integrated with a fluidic sample delivery. We will then validate the platform with a panel of key human pathogens displaying different drug susceptibility profiles and determine the minimum inhibitory concentration (MIC) of antibiotics, the sensitivity of the assay and the functionality of the assay in human body fluids. Finally, we will test the platform in clinical specimens from patients with suspected bacteremia at different stages of sample processing and compare the results with standard AST for microbial identification and susceptibility testing. It is anticipated that the proposed approach reduces the turnaround time of the AST to less than 1 hour compared to 3-4 days using conventional AST methods. The proposed project advances our knowledge of developing new, rapid and low-cost diagnostic methods ($5 per test) based on color sensing materials and will generate innovations and secure commercialization. The potential to reduce the time-to-result for phenotypic AST at a low-cost would have significant economic impact on the Canadian health system.

Sara Mahshid

Dao Nguyen

At the heart of the matter - Speckle tracking echocardiography in lupus mothers and their offspring

Women with systemic lupus erythematosus (SLE) have a high risk of placentamediated complications, which can lead to substantial cardiac morbidities in affected women and their offspring. In addition, maternal autoantibodies, which are actively transferred across the placenta during pregnancy, can affect the cardiovascular health of SLE offspring. Hydroxychloroquine (HCQ) is effective in preventing adverse pregnancy outcomes in SLE and might be beneficial in preventing fetal cardiovascular damage mediated by maternal autoantibodies. However, there are concerns that HCQ might cause maternal and neonatal cardiac toxicity. A novel imaging technique (i.e. speckle tracking echocardiography), which allows early identification of cardiac dysfunction, has proven superior to any other in assessing cardiac function in mothers and neonates experiencing placenta-mediated complications and in identifying drug cardiotoxicity. Yet, there has been no study using speckle tracking echocardiography to evaluate the cardiovascular health of pregnant SLE women and their offspring, as well as the potential adverse cardiac effect of HCQ. Moreover, due to unavailability of assays, HCQ dosing in SLE is generally done blindly, without checking drug levels. To fill these key knowledge gaps, we aim to: 1) assess the impact of placenta-mediated complications on maternal and neonatal cardiac function, 2) evaluate if HCQ exposure (as measured by whole-blood levels) is associated with maternal and neonatal outcomes including cardiac toxicity, and 3) determine the effect of maternal autoantibodies on neonatal cardiac function. Ultimately, our proposal will help optimize reproductive and cardiovascular outcomes in lupus women and their offspring.

Evelyne Vinet

Lawrence Rudski

MI4 - MNI COLLABORATIVE SEED FUND GRANT

LEAD PIs

Inflammation-mediated white matter injury in pediatric encephalopathies

Brain tissue destruction in newborns/young children, termed infantile hypoxic encephalopathy (IHE), often occurs consequent to systemic infectious and metabolic disorders and results in permanent neurologic sequela (cerebral palsy). A pathologic hallmark is injury to oligodendrocytes (OLs) – the cell type that produces myelin processes that wrap nerve fibers, allowing efficient electrical conduction. Such injury reflects the combined effects of inflammation and lack of oxygen/nutrients at injury sites. Recovery requires tissue repair by progenitor cells (termed OPCs) that can produce new OLs/myelin. Our aims are to: 1) perform functional studies on OL lineage cells derived from human surgically resected brain samples to determine their vulnerability to immune mediators (effector cytokines, glutamate) and metabolic stress (low glucose) as a function of donor age and cell differentiation stage. Concurrent bioinformatics analyses of bulk RNA sequenced cells will be used to identify contributing molecular mechanisms. 2) show that molecular signatures of injured OL lineage cells (defined by our in vitro studies) are represented in situ. We will use tissue sections from cases of IHE and controls for this analysis. Our results will direct the search for therapies that can protect OL lineage cells from injury and promote repair.

Jack Antel

Myriam Srour

MI4 - MGH COLLABORATIVE SEED FUND GRANT

LEAD PIs

A Rabbit Prosthetic Joint Infection Model for Evaluation of Nano-Layered Antimicrobial Surface Coatings

Infection following joint replacement surgery is increasing in incidence and is a devastating complication. Only a small quantity of bacteria introduced inadvertently during surgery can inoculate the surgical wound and implants, leading to infection. Bacteria quickly attach themselves to the implant surfaces and can evade the human immune system by growing in a protective slime layer called biofilm. Once infection ensues, the joint becomes painful and the patient inevitably requires multiple surgeries to clean or remove the implants. Consequently, infection is a serious complication that leads to a poor outcome.

Antimicrobial surface coatings are a promising strategy to help prevent prosthetic joint infections. In particular, silver has well-known antimicrobial properties and has already been used to coat selective medical devices. Unfortunately, successful inhibition of bacteria by the silver on orthopedic implants has been tempered by the body’s local inflammatory reaction to silver which inhibits bone from growing into the implants, leading to failure. The proposed research explores a special fabrication technique using nanoparticles to construct a titanium dioxide coating that can minimize the undesired local tissue inflammation while maintaining the antimicrobial properties. Various configurations of this layering technology will be tested in a rabbit model to demonstrate proof of concept.

Adam Hart

Maryam Tabrizian

GHP-MI4 Steinberg Seed Fund Grant

Seed Fund Grant Title	Lead PI
The contribution of stigma among sexual minority men to HIV transmission in sub-Saharan Africa. To successfully eliminate AIDS as a public health threat, we must address the unmet prevention needs and disproportionately high HIV burden experienced by key populations –groups at high risks of HIV acquisition and transmission. These elevated risks are exacerbated by widespread stigma and discrimination that act as barriers to accessing HIV services, especially among gay, bisexual, and other sexual minority men. Stigma refers to discrimination, prejudice, negative attitudes, and abuse directed at sexual minority men based on their identity and behaviors. Stigma could partly drive population-level HIV transmission beyond sexual minority men in sub-Saharan Africa since most of them also report female sexual partners. The overarching aim of this project is to estimate the population-level impact of stigma to HIV transmission among sexual minority men in sub-Saharan Africa. To do so, we will conduct an individual-based meta-analysis of cohort studies. By pooling available studies, we will uncover the pathways through which stigma influences HIV acquisition and empirically quantify its impact. HIV and human rights are inextricably linked. By providing critical evidence on the role of stigma in perpetuating HIV risks among sexual minority men, this project will inform stigma-based HIV prevention among key populations in sub-Saharan Africa and beyond.	Mathieu Maheu-Giroux

Seed Fund Grant Title

Lead PI

The contribution of stigma among sexual minority men to HIV transmission in sub-Saharan Africa.

To successfully eliminate AIDS as a public health threat, we must address the unmet prevention needs and disproportionately high HIV burden experienced by key populations –groups at high risks of HIV acquisition and transmission.

These elevated risks are exacerbated by widespread stigma and discrimination that act as barriers to accessing HIV services, especially among gay, bisexual, and other sexual minority men. Stigma refers to discrimination, prejudice, negative attitudes, and abuse directed at sexual minority men based on their identity and behaviors. Stigma could partly drive population-level HIV transmission beyond sexual minority men in sub-Saharan Africa since most of them also report female sexual partners.

The overarching aim of this project is to estimate the population-level impact of stigma to HIV transmission among sexual minority men in sub-Saharan Africa. To do so, we will conduct an individual-based meta-analysis of cohort studies. By pooling available studies, we will uncover the pathways through which stigma influences HIV acquisition and empirically quantify its impact.

HIV and human rights are inextricably linked. By providing critical evidence on the role of stigma in perpetuating HIV risks among sexual minority men, this project will inform stigma-based HIV prevention among key populations in sub-Saharan Africa and beyond.

Mathieu Maheu-Giroux

MI4 Seed Fund Grants - Round 2

In May 2020, MI4 was pleased to announce 5 award winners for Round 2 of the MI4 Seed Fund Grant program. A total of 23 applications were received. All applications were peer reviewed by an independent Scientific Review Committee composed of researchers external to the McGill community.

The awarded grants are as follows:

Seed Fund Grant Title	Lead PIs
CCR5 gene editing with antiviral genes to cure HIV-1 infection Drug therapies for HIV can prevent the development of AIDS but cannot eliminate the virus and daily medication comes with many side effects. A cure for HIV remains a major unmet medical need and an unrealized dream for many people living with or affected by HIV. So far, only two people have been cured of HIV using bone marrow transplants from donors with natural resistance to HIV, resulting from a mutation in a gene called CCR5. Due to the lack of compatible resistant donors and the risks associated with cell transfer between individuals, this procedure cannot be used for most HIV infected people. However, it is possible to use a similar procedure, in which a person's own bone marrow cells are modified to mimic the CCR5 mutation. A limitation of this approach is that some types of HIV can infect cells with the CCR5 mutation. Using cells and viruses from different groups of people living with HIV, we will categorize which people are not likely to be cured using CCR5 modification alone. We will also use antiviral genes in combination with CCR5 modification to identify a method that can be used to cure all people living with HIV.	Anne Gatignol Jean-Pierre Routy
Integrating polygenic risk scores, machine learning and mouse models to develop predictive tools and therapeutics for severe dengue disease Dengue is a mosquito-borne viral infection that global warming has brought to over 40% of the world’s population and to the doors of Canada. Infection with dengue virus results in a spectrum of diseases from dengue fever to severe and even fatal forms of the disease, particularly in children. The lack of specific treatments compounded by the difficulty of predicting which patients will have a severe response render the situation increasingly worrisome. This proposal builds on a novel view of dengue progression that implicates a particular viral protein, NS1, and host lipid metabolism to address the challenges of severe dengue infections. It leverages genetic epidemiology, modern analytical approaches, large patient cohorts, as well as a team of international experts on the genetics and function of lipids, mathematical modelling, dengue genetic epidemiology, virology, immunology and modelling in mice to provide new perspectives for the management of severe dengue. These studies will identify specific biomarkers to predict and optimize treatment severe dengue. In addition, our project will produce new mouse models of severe dengue disease that will be studied before experiments in humans, some of which will examine cholesterol-modulating drugs for the treatment of severe dengue.	Jamie Engert Silvia Vidal
The Pragmatic Observation of Labor, Exercise Tolerance, and Respiratory Impairment After Treatment of TB Tuberculosis (TB) is an infectious disease spread through the air. In 2018, 8.5 million people became sick with TB of the lungs, pulmonary TB (PTB). At least 1 in 3 people who complete PTB treatment are left with difficulty breathing due to destruction and scarring of lungs from the infection. In 2018, this mounted to around 2 million people. In low- and middle-income countries (LMICs) that account for the majority of global TB burden, 50%-70% of the workforce have jobs requiring heavy physical work and PTB is mostly a disease of working age people. It is likely that many individuals cured of PTB in LMICs are physically unable to return to their pre-illness occupation, or income earning, due to PTB-related chronic lung disease—but very little research has focused on this area. We address two major gaps in our study: (1) we characterize the impact of post-PTB lung disease on work and income; and (2) we explore how this lung disease can be managed in resource-limited LMIC settings where PTB mostly affects poor populations who can’t afford the medications commonly used to treat breathing disorders. Our work will pave the way to conduct urgently needed trials on this topic.	Faiz Ahmad Khan Dennis Jensen
A stem cell-based microfluidics approach to mine the immunomodulatory activity of the gut epithelial secretome Chronic diseases of the intestine such as inflammatory bowel disease and irritable bowel syndrome continue to rise in developing nations. It is now clear that immune-microbial interactions in the intestine play a central role in controlling these diseases. These interactions are exquisitely controlled by a single layer of epithelial cells that actively regulate how the immune system reacts to infection. However, a comprehensive examination of epithelial-derived factors with immunomodulatory activity has been limited by the lack of scalable and quantitative approaches that recapitulates realistic gut behaviour. Here we propose to build a novel organ-on-a-chip platform that uses stem cells to generate the gut epithelium and identify the arsenal of factors secreted in response to microbial insult. This approach will be paired with functional tests that examine how these factors impact immune cell activation. Our proposal takes advantage of cross disciplinary expertise in tissue engineering, intestinal stem cell biology, microfluidics technology and immunology to discover new pathways by which host-microbe interactions educate the immune system. Furthermore, it will provide a roadmap for defining, in unprecedented fashion, how gut-microbe interactions impact human health.	Irah King Christopher Moraes
Targeting oncosome educated neutrophil subsets to curtail breast cancer metastasis To grow as a primary tumor and spread into distant organs (metastasize), breast cancer cells must disable and corrupt the body’s natural defenses (immunity), especially the white blood cells. Neutrophils are the most numerous white blood cells, which are responsible for inflammation that often stimulates growth of disseminated cancer cells, rather than killing them. Neutrophils in cancer patients and mice bearing disseminated tumours are different than those found when there is no tumour, or not disseminated cancer. They are more ‘immature’ and possess the capacity to form mesh like structures (NETs) that stiffen the tissue and facilitate cancer spreading. To do so, neutrophils must receive signals from cancer cells, but it is unclear what these signals are. In mice with cancer, neutrophils ingest and accumulate tiny fragments of cancer cell ‘bodies’, known as extracellular vesicles (EVs), exosomes or oncosomes, which contain cancer-specific molecules (including DNA and RNA). We propose that these cancer-derived molecular packets may selectively enter immature neutrophils and activate abnormal cancer-like functions in them resulting in increased cancer dissemination. In this proposal we will study how EVs are ingested and how they change (‘educate’) neutrophils to become pro-metastatic.	Peter Siegel and Janusz Rak

Seed Fund Grant Title

Lead PIs

CCR5 gene editing with antiviral genes to cure HIV-1 infection

Drug therapies for HIV can prevent the development of AIDS but cannot eliminate the virus and daily medication comes with many side effects. A cure for HIV remains a major unmet medical need and an unrealized dream for many people living with or affected by HIV. So far, only two people have been cured of HIV using bone marrow transplants from donors with natural resistance to HIV, resulting from a mutation in a gene called CCR5. Due to the lack of compatible resistant donors and the risks associated with cell transfer between individuals, this procedure cannot be used for most HIV infected people. However, it is possible to use a similar procedure, in which a person's own bone marrow cells are modified to mimic the CCR5 mutation. A limitation of this approach is that some types of HIV can infect cells with the CCR5 mutation. Using cells and viruses from different groups of people living with HIV, we will categorize which people are not likely to be cured using CCR5 modification alone. We will also use antiviral genes in combination with CCR5 modification to identify a method that can be used to cure all people living with HIV.

Anne Gatignol

Jean-Pierre Routy

Integrating polygenic risk scores, machine learning and mouse models to develop predictive tools and therapeutics for severe dengue disease

Dengue is a mosquito-borne viral infection that global warming has brought to over 40% of the world’s population and to the doors of Canada. Infection with dengue virus results in a spectrum of diseases from dengue fever to severe and even fatal forms of the disease, particularly in children. The lack of specific treatments compounded by the difficulty of predicting which patients will have a severe response render the situation increasingly worrisome. This proposal builds on a novel view of dengue progression that implicates a particular viral protein, NS1, and host lipid metabolism to address the challenges of severe dengue infections. It leverages genetic epidemiology, modern analytical approaches, large patient cohorts, as well as a team of international experts on the genetics and function of lipids, mathematical modelling, dengue genetic epidemiology, virology, immunology and modelling in mice to provide new perspectives for the management of severe dengue. These studies will identify specific biomarkers to predict and optimize treatment severe dengue. In addition, our project will produce new mouse models of severe dengue disease that will be studied before experiments in humans, some of which will examine cholesterol-modulating drugs for the treatment of severe dengue.

Jamie Engert

Silvia Vidal

The Pragmatic Observation of Labor, Exercise Tolerance, and Respiratory Impairment After Treatment of TB

Tuberculosis (TB) is an infectious disease spread through the air. In 2018, 8.5 million people became sick with TB of the lungs, pulmonary TB (PTB). At least 1 in 3 people who complete PTB treatment are left with difficulty breathing due to destruction and scarring of lungs from the infection. In 2018, this mounted to around 2 million people. In low- and middle-income countries (LMICs) that account for the majority of global TB burden, 50%-70% of the workforce have jobs requiring heavy physical work and PTB is mostly a disease of working age people. It is likely that many individuals cured of PTB in LMICs are physically unable to return to their pre-illness occupation, or income earning, due to PTB-related chronic lung disease—but very little research has focused on this area. We address two major gaps in our study: (1) we characterize the impact of post-PTB lung disease on work and income; and (2) we explore how this lung disease can be managed in resource-limited LMIC settings where PTB mostly affects poor populations who can’t afford the medications commonly used to treat breathing disorders. Our work will pave the way to conduct urgently needed trials on this topic.

Faiz Ahmad Khan

Dennis Jensen

A stem cell-based microfluidics approach to mine the immunomodulatory activity of the gut epithelial secretome

Chronic diseases of the intestine such as inflammatory bowel disease and irritable bowel syndrome continue to rise in developing nations. It is now clear that immune-microbial interactions in the intestine play a central role in controlling these diseases. These interactions are exquisitely controlled by a single layer of epithelial cells that actively regulate how the immune system reacts to infection. However, a comprehensive examination of epithelial-derived factors with immunomodulatory activity has been limited by the lack of scalable and quantitative approaches that recapitulates realistic gut behaviour. Here we propose to build a novel organ-on-a-chip platform that uses stem cells to generate the gut epithelium and identify the arsenal of factors secreted in response to microbial insult. This approach will be paired with functional tests that examine how these factors impact immune cell activation. Our proposal takes advantage of cross disciplinary expertise in tissue engineering, intestinal stem cell biology, microfluidics technology and immunology to discover new pathways by which host-microbe interactions educate the immune system. Furthermore, it will provide a roadmap for defining, in unprecedented fashion, how gut-microbe interactions impact human health.

Irah King

Christopher Moraes

Targeting oncosome educated neutrophil subsets to curtail breast cancer metastasis

To grow as a primary tumor and spread into distant organs (metastasize), breast cancer cells must disable and corrupt the body’s natural defenses (immunity), especially the white blood cells. Neutrophils are the most numerous white blood cells, which are responsible for inflammation that often stimulates growth of disseminated cancer cells, rather than killing them. Neutrophils in cancer patients and mice bearing disseminated tumours are different than those found when there is no tumour, or not disseminated cancer. They are more ‘immature’ and possess the capacity to form mesh like structures (NETs) that stiffen the tissue and facilitate cancer spreading. To do so, neutrophils must receive signals from cancer cells, but it is unclear what these signals are. In mice with cancer, neutrophils ingest and accumulate tiny fragments of cancer cell ‘bodies’, known as extracellular vesicles (EVs), exosomes or oncosomes, which contain cancer-specific molecules (including DNA and RNA). We propose that these cancer-derived molecular packets may selectively enter immature neutrophils and activate abnormal cancer-like functions in them resulting in increased cancer dissemination. In this proposal we will study how EVs are ingested and how they change (‘educate’) neutrophils to become pro-metastatic.

Peter Siegel and Janusz Rak

MI4 Seed Fund Grants - Round 1

In June 2019, MI4 was thrilled to announce the award winners for Round 1 of MI4 Seed Fund Grants. A total of 43 applications were received. All applications were peer reviewed by an independent Scientific Review Committee composed of 25 researchers external to the McGill community.

As well, MI4 is pleased to be collaborating with the Montreal Neurological Institute (MNI) and the Goodman Cancer Research Centre (GCRC) in this first round of Seed Fund Grants, enabling the funding two additional collaborative Seed Fund Grants: in neurological disease and in immuno-oncology, respectively.

The awarded grants are as follows:

Seed Fund Grant Title	Lead PIs
Nature-inspired nanostructures: designing next generation antimicrobial biomaterials Lay Summary Our therapeutic arsenal against bacterial infections is rapidly shrinking, as drug resistance spreads and the antibiotic development pipeline runs dry. Novel technologies that can minimize the transmission of potential pathogens, particularly drug resistant bacteria, can be part of the solution to these shortcomings. One such class of technology was recently identified by studying the anti-bacterial properties of dragonfly and cicada wings, which contain beautifully-formed and intricate nanoscale “beds of nails” that kill by physical contact rather than by the use of antimicrobial molecules. Subsequent studies suggest that certain high aspect ratio nanomaterials, termed “mechano-bactericidal” nanostructures, can mimic this behaviour and impart critical microbial damage via their nanoscale shape, while leaving mammalian cells unharmed. As with any research field in its infancy, there exists significant debate and contradictions regarding underlying mechanisms and, by extension, the optimal design strategy to maximize antibacterial performance of these nanostructures. This research will investigate antibacterial interactions between bacterial cells and nanopillars synthesized on various materials. A comprehensive understanding of cell-surface interactions will improve insights for future designs of antibacterial surfaces. As antibacterial surfaces that do not rely primarily on diffusion of antibacterial agents, mechano-bactericidal nanotopographies offer opportunities for next-generation sustainable antimicrobial materials.	Nathalie Tufenkji Dao Nguyen
Seed Fund Grant Title	Lead PIs
Integration of genomics and metagenomics for the surveillance of the Lyme disease vector Ixodes scapularis in Canada and the USA Lay Summary The Public Health Agency of Canada anticipates increased burden of disease (i.e. Lyme disease) as a result of thermal stress and more frequent extreme weather events. Lyme disease is a severe infectious illness caused by the bacterium Borrelia burgdorferi and transmitted by tick vectors (Ixodes scapularis). There is no vaccine against Lyme disease whereas approximately 20 % of people who are treated with the recommended antibiotics will develop chronic disabling disease symptoms from fatigue, joint and muscle aches to cognitive dysfunction. Both the range of ticks and Lyme disease have been rapidly expanding in Canada, which has led to the establishment of a national medical surveillance program and prompted investigations in Lyme disease as research priority. Furthermore, ticks are responsible for the transmission of other pathogens of relevance to health, including fungi, protozoan and bacterial species. Whereas climate change is a known determinant for the expansion of this disease, little is known about the genetic and molecular mechanisms acting on the vector that underlie the increased risk of disease. This proposal will leverage on novel genomic technologies and an international team of experts in genomics, vector biology, bacteria evolution and diagnostics to address the challenge of Lyme disease. We will examine the extent of vector genomic variation in two endemic areas, namely Vermont and Québec Eastern Townships and how this relates to the rate of Borrelia infection. We will define the full spectrum of pathogenic and symbiotic microbial communities (the microbiome) colonizing the vector, and investigate the impact of vector genomic variation on the composition of these communities. In turn, we will address whether the vector microbiome influences the risk of vector infection and pathogen transmission. These studies will lead not only to a better understanding of the relation between the vector, the pathogen that it transmits and its microbiome in disease emergence but also to the identification of new molecular markers for improved disease surveillance and diagnostic. Moreover, by bringing together investigators in areas of disease activity, this research will enhance capacity for intervention against the increased threat of tick-borne infections in North America.	Michael B. Reed Ioannis Ragoussis
Seed Fund Grant Title	Lead PIs
A Deadly Combination: Air Pollution and TB in India Lay Summary Tuberculosis (TB) affects more than 10 million people each year and kills more than 1.7 million people annually. Pollution is the largest environmental cause of disease and premature death in the world today, with particulate air pollution alone contributing to more than 4 million premature deaths annually. India is the epicenter of the global TB epidemic, accounting for 25% of estimated deaths. Adding insult to injury, India also has some of the worst air quality in the world which adds an additional burden to patients already struggling with a crippling respiratory illness. Due to paucity of evidence, the TB field has yet to acknowledge outdoor air pollution as an important risk factor. In this pilot study, we will first use personal aerosol monitors to characterize personal exposures to fine particulate air pollution (PM2.5) among 100 active TB patients in New Delhi as well as in Udupi town, Karnataka, to contrast exposures experienced by TB patients in a high polluted versus less polluted area of India. As a second objective, we will develop a new model to predict neighbourhood-level air pollution concentrations based on street-level and satellite imagery. This model will be developed using modern “deep learning” methods applied to large databases of paired image-exposure information collected across our research locations. The final model will serve as a cost-effective resource to estimate environmental exposures for large numbers of study participants in our subsequent follow-up studies outlined in future grant applications (section 4). In summary, TB and air pollution both contribute substantially to the overall global burden of disease, but the combined impact of these risk factors has been largely overlooked. We aim to change this through a new interdisciplinary research collaboration (with an early career investigator in lead), starting with a seed grant that will enable the development of a state-of-the-art model that will allow us to scale exposure estimation to future, larger, cohort study on how pollution affects TB outcomes.	Madhukar Pai Scott Weichenthal
Seed Fund Grant Title	Lead PIs
Design of a Rapid Point-of-Care PCR device for the diagnosis and management of HIV, HCV and other infectious diseases for key vulnerable populations in real-world settings Lay Summary The World Health Organization advocates for increased accessibility of point-of-care (POC) diagnostics for HIV-1 and related infections (including hepatitis C virus (HCV)) in hard-to-reach settings that lack laboratory infrastructure. Drs. Trifiro, Kirk and Paliouras have re-designed PCR technology towards the development of a true POC, rapid, portable and battery-powered device, to provide “label-free” quantitative detection of microbial infections. In this proposal, we intend to develop an integrated “sample-to-result” diagnostic test for the detection and quantification of HIV and HCV using the patent-approved and proprietary Plasmonic PCR platform. The performance of Plasmonic PCR will be compared to government-standard qPCR viral load detection assays. The Plasmonic PCR device will be evaluated in key vulnerable provincial populations, including the MUHC cohort of new migrants, refugees and asylum seekers, the Canadian Co-Infection Cohort of HIV/HCV co-infected persons, and the Primary HIV cohort of men who have sex with men and people who inject drugs. With the success of this study, we intend to apply the technology to other viral and microbial infections, (e.g. human papilloma virus and tuberculosis) as part of a multi-disease/multiplex mobile rapid POC testing strategy.	Bluma Brenner Nadine Kronfli
Seed Fund Grant Title	Lead PIs
Investigation of the functionality of anti-Respiratory Syncytial Virus specific antibodies Lay Summary Human respiratory syncytial virus (RSV) is an important cause of lower respiratory tract disease. It infects the respiratory tract of most children before the age of 2 and it is the greatest cause of infant hospitalisation worldwide. For most children and infants, it causes symptoms that are no more serious than a cold. However, in some cases, children develop bronchiolitis, which requires hospitalization, and can be life threatening. At this time, it is not clear what immune responses are best able to control this virus so there is no vaccine and no drugs that can treat RSV infections once they have started. However, antibodies (Abs) are an interesting candidate. A commercially available monoclonal Ab (mAb) called pavilizumab is in use; however, it can only be used preventatively to protect high risk children from infection with RSV. Abs have two main functional domains, the Fab domain recognizes a part of a pathogen or virus (antigen) and the second, termed the Fc domain, allows Abs to interact with a wide range of immune cells, that once activated, can exert antiviral functions. We have developed a platform of tests that measure these Fc-dependent antiviral activities. To make these tests specific for RSV we require a source of Ab that recognizes RSV and a target cell that expresses the RSV antigens expressed on infected cells. In this proposal, we will engineer RSV antigen positive target cells and acquire biological fluid samples from nasopharyngeal swabs that are used to diagnose RSV infection in children. After quantifying the amount of Ab in these samples, we will examine the function of the RSV-specific Abs in the biological fluid of samples from infected children. This information will be compared to the preventative Ab, pavilizumab. The project will ascertain how Abs to RSV that develop in children with respiratory illness severe enough to require hospitalization differ from pavilizumab. The project will generate information that can be used to select effective therapeutic Abs and assess the effectiveness of novel vaccines that are being designed to protect against RSV infection.	Selena Sagan Nicole Bernard
Seed Fund Grant Title	Lead PIs
The impact of the microbiome in shaping host defense against tuberculosis Lay Summary Despite more than 100 years since the discovery of Mycobacterium tuberculosis (Mtb), this organism remains one of the most successful human pathogens. Approximately 2 million people die of TB annually and 8 to 10 million new cases of active tuberculosis occur each year. Millions of individuals worldwide are treated with anti-tuberculosis therapy (ATT) to control active disease or prevent recrudescence of latent Mycobacterium tuberculosis (Mtb) infection. Although these antibiotics are effective at decreasing TB-associated mortality, they do not lead to a sterilizing cure and, paradoxically, may leave individuals more susceptible to reinfection. Furthermore, these antibiotics may have previously unrecognized consequences on the commensal microbiota that perform important roles in host defense. The central hypothesis of the current proposal is that anti-TB antibiotics compromise microbiota-immune crosstalk that prevents the generation of permanent immunity to Mtb. Our work will define the intersection between the microbiome and the immune response to Mtb infection and have rapid clinical impact for this devastating disease.	Maziar Divangahi Jianguo Xia
Seed Fund Grant Title	Lead PIs
Apta-Nanosurface Fluidic Assay for Specific and Rapid Detection of Parasites via a Labelfree Electrical Readout Lay Summary Accurate, robust and rapid surveillance of water-borne parasites has significant impact on public health especially among vulnerable populations. The impact of these debilitating diseases caused by parasites are enormous, affecting over a million people across North America annually. The slow turnaround time for traditional identification techniques and labor-intensive methods such as microscopy is a driving factor to develop new assays and methods for rapid and accurate identification at the point of need. We aim to develop an ultrasensitive electrical apta-nano assay for rapid identification of water-borne parasites such as Cyclospora, Cryptosporidium and Giardia. The proposed assay is based on a novel hierarchical gold/graphene nanostructured platform that provides an ultra-sensitive, specific and label-free electrical readout upon capture of target parasites on the surface-immobilized aptamer. We utilize this nanostructured platform and the aptamer recognition element in conjunction with parallel nano/microfluidic sample delivery for efficient delivery of the sample solution and buffers in a multiplex manner. First, we develop a specific biorecognition element by designing aptamers specific towards Cyclospora, Cryptosporidium and Giardia. Second, we develop a sensitive electrical apta-nano readout by fabricating hierarchical 3D gold/graphene nanostructures and study the surface functionalization with aptamer, and test its unique label-free electrical behavior in the presence of Cyclospora, Cryptosporidium and Giardia. Third, we develop on-chip multiplexity from unprocessed samples by fabricating parallel fluidic channels with micro/nanofilter connected to the electrical apta-nano readout and validate its performance with Cyclospora, Cryptosporidium and Giardia from environmental samples and specimens from patients. In close collaboration with MUHC medical microbiology laboratory, we compare the performance of prototype with the samples and data submitted for the parasites panel.	Sara Mahshid Momar Ndao
Seed Fund Grant Title	Lead PIs
Targeting the MNK1/2-eIF4E axis in postpartum breast cancer liver metastasis Lay Summary Tackling an unmet clinical need: Cancer is a devastating diagnosis for patients, but even more so for young mothers diagnosed with postpartum breast cancer (PPBC), which tends to be metastatic. The latter means that mothers must put caring for their newborns on hold, while they undergo surgery, post-operative recovery, and additional aggressive chemotherapy, as PPBC cases are often considered high risk for recurrence. The physical, and psychological burden does not affect only the woman diagnosed with breast cancer, but also her entire family. Clearly, more research needs to be focused on this subtype of breast cancer. A major goal of the del Rincon lab has been to accelerate therapeutic discoveries for women diagnosed with PPBC and develop novel therapies for this metastatic disease. Our clinical data show that women diagnosed with PPBC are at increased risk for liver metastasis relative to nulliparous women. The Brodt lab has extensive experience in the study of the biology of liver metastasis. Here the Brodt and del Rincon labs have teamed up to elucidate the mechanism(s) underlying the increased propensity of PPBC for liver metastasis. We postulate that the MNK1/2 axis plays a role in this predilection and will use MNK1/2 inhibitors to inhibit liver metatsasis in a pre-clinical model of PPBC. Moreover, we propose to use MNK1/2 inhibitors in combination with immunotherapy in an effort to potentiate an immune attack on metastatic PPBC. MNK1/2 have entered clinical trials, thus we are confident that the discoveries made by our team could have important translational applications in the foreseeable future. Scientists, Clinicians and Advocates team up to fight postpartum breast cancer metastasis: We are fortunate to have the full support of a network of scientists, clinicians, and patient advocates, who are dedicated to ensuring the successful completion of the proposed, and future, work. Funding will be invaluable to help Dr. del Rincon’s career development as an independent breast cancer researcher.	Sonia del Rincon Pnina Brodt
Seed Fund Grant Title	Lead PIs
Targeting the mitophagy pathway to treat sepsis-induced organ dysfunction Lay Summary Sepsis is a leading cause of death in the intensive care units and is responsible for ten thousand deaths in Canada each year. Skeletal muscle dysfunction manifested as fiber atrophy and weakness is a primary clinical observation in critically ill septic patients. Long-term ramifications of limb muscle weakness include functional impairment and poor quality of life. Sepsis-induced skeletal muscle atrophy and weakness are associated with accumulation of damaged and dysfunctional mitochondria (the main source of cellular energy). In normal skeletal muscles, dysfunctional mitochondria are selectively recycled through the autophagy pathway, a process known as mitophagy. In this process, autophagosomes recognize dysfunctional mitochondria primarily through the PINK1-Parkin pathway. This process is inhibited by a protein called P53 which retains Parkin in the cytosol. The main aim of this proposal is to evaluate the therapeutic potentials of enhancing mitophagy by overexpressing Parkin and PINK1 selectively in skeletal muscles or by inhibiting p53 on mitochondrial function, atrophy and depressed contractility in a mouse model of sepsis that simulates human sepsis. To achieve this aim, we have assembled an experienced team of leading investigators in the fields of skeletal muscle biology and mitochondrial structure and function, Hussain, and McBride, who have extensive expertise in skeletal muscle diseases, and mitochondrial function. Overexpression of Parkin and PINK1 will be achieved by injection of adeno-associated viruses in limb muscles and these muscles will be examined under control and septic conditions. P53 inhibition will be achieved by using mice defective in muscle p53 or by using a pharmacological p53 inhibitor. Mitochondrial function and morphology as well as muscle fiber size and contractile performance will be evaluated in both control and septic mice. We are certain that when the project is completed the knowledge that will emerge will be foundational to the development of novel strategies that rely on PINK-1-Parkin pathway activation in septic skeletal muscles. This activation could result in the prevention, possibly even the reversal, of muscle dysfunction in septic patients. The project, therefore, represents research that has rich translational potential for improved care of critically ill patients.	Sabah Hussain Heidi McBride
Seed Fund Grant Title	Lead PIs
The combi-targeting concept: Engineering small molecules to target cell signaling, kill tumour cells and stimulate the immune system Lay Summary Despite the significant progress in our understanding of the multiple targets associated with the complex signaling networks that characterize drug resistance in the advanced stages of cancer, our approaches to drug discovery have widely favored the « one-drug, one-gene » strategy. According to this assumption, the selectivity of a drug for its cognate target is directly related to its anti-tumour activity. Paradoxically, nearly two decades of work with this hypothesis, have shown that many clinically successful modulators designed to be target-specific were classified as “multi-targeted drugs” a posterori and these exhibited potent activity in the clinic. Analysis of 974 anticancer agents from 1995 to 2007, in developmental phases (phase I to registration) led to an overall attrition rate as high as 82%. However, this rate fell to only 52% when the analysis was restricted to a subset of multi-targeted drugs. There thus needs to be a paradigm shift in our approach to anti-cancer drug discovery. The complexity of the signaling networks that drive tumour progression imposes a rather one-two, or three-punch approach. In this context, we developed a novel approach termed « combi-targeting » that addresses the genetic complexity and the target heterogeneity of solid tumours in the advance stages. The combi-targeting concept is a McGill-developed drug discovery strategy that seeks to design single molecules termed “combi-molecules to block the adverse effects of the mumours in multiple fronts. One of the major problem with tumour cells is that they can hide from the immune system. Here we are using our double-sword approach to force them to express protein that will render them visible by the immunize system and at the same time we program them to open the eye of the immune system so that it can see them and destroy them. This is a strategy that has never been tried before in drug design against cancer.	Bertrand Jean-Claude Moulay Alaoui-Jamali

MI4 - MNI Collaborative Seed Fund Grant

Seed Fund Grant Title	Lead PIs
Unraveling the microbial contributions to Parkinson’s Disease Lay Summary Parkinson's disease (PD) is a common neurodegenerative disease that affects 1-2 per 1000 of the general population. However, PD prevalence is increasing with age and PD affects a striking 1% of the population above 60 years. The etiology of PD is unknown but strong experimental and epidemiological data supports PD as an inflammatory disease that originates from the gut. Based on findings from human populations and experiments in mouse model systems, we propose that the cause of inflammatory dysregulation in PD patients is infection with common pathogens that alter the gut mucosal immune balance. In support of this hypothesis, we and others have shown that the same inherited genetic mutations are shared between inflammatory bowel disease (IBD), leprosy reactions (characterized by systemic dysregulated inflammation leading to nerve damage), and PD. Moreover, we have shown that mice engineered to carry a known PD susceptibility gene will develop PD-like neurological and clinical symptoms following infection with a gut pathogen. The pathological symptoms in these mice only develop after the initial gut infection has been cleared. This is a stunning parallel to leprosy reactions that manifest in a majority of patients only after microbiological cure of the M. leprae pathogen. In the present application, we will expand on the role of infection in the etiology of PD by employing cellular and animal models established in our laboratories. We will conduct a survey of select pathogens for their impact on immune mechanism linked to PD and their ability to induce Parkinson-like symptoms in mice with a genetic PD-susceptibility background. These experiments will pinpoint the types of pathogens that are candidates for being causative agents of PD and lay the foundation for future pre-clinical and clinical studies of PD prevention.	Heidi McBride Erwin Schurr

Seed Fund Grant Title

Lead PIs

Unraveling the microbial contributions to Parkinson’s Disease

Lay Summary

Parkinson's disease (PD) is a common neurodegenerative disease that affects 1-2 per 1000 of the general population. However, PD prevalence is increasing with age and PD affects a striking 1% of the population above 60 years. The etiology of PD is unknown but strong experimental and epidemiological data supports PD as an inflammatory disease that originates from the gut.

Based on findings from human populations and experiments in mouse model systems, we propose that the cause of inflammatory dysregulation in PD patients is infection with common pathogens that alter the gut mucosal immune balance. In support of this hypothesis, we and others have shown that the same inherited genetic mutations are shared between inflammatory bowel disease (IBD), leprosy reactions (characterized by systemic dysregulated inflammation leading to nerve damage), and PD. Moreover, we have shown that mice engineered to carry a known PD susceptibility gene will develop PD-like neurological and clinical symptoms following infection with a gut pathogen. The pathological symptoms in these mice only develop after the initial gut infection has been cleared. This is a stunning parallel to leprosy reactions that manifest in a majority of patients only after microbiological cure of the M. leprae pathogen.

In the present application, we will expand on the role of infection in the etiology of PD by employing cellular and animal models established in our laboratories. We will conduct a survey of select pathogens for their impact on immune mechanism linked to PD and their ability to induce Parkinson-like symptoms in mice with a genetic PD-susceptibility background. These experiments will pinpoint the types of pathogens that are candidates for being causative agents of PD and lay the foundation for future pre-clinical and clinical studies of PD prevention.

Heidi McBride

Erwin Schurr

MI4 - GCRC Collaborative Seed Fund Grant

Seed Fund Grant Title	Lead PIs
Humanized Mouse Models to Untangle Mechanisms of Immune Checkpoint Inhibitors- Immune Related Adverse Events and Effects of their treatment in Tumor Biology Lay Summary The concept of treating cancer through the activation of the patient’s own immune system to kill tumor cells led to the development of immune checkpoint inhibitors (ICI). These drugs revolutionized the field of oncology as they control cancers with otherwise very poor prognosis. However, as a consequence of immune activation, up to 50% of cancer patients treated with ICI develop immune related adverse events (irAE, e.g. inflammation of the colon, lungs, joints). The severity of these irAE often requires the use of drugs to control the damage associated with excessive immune activation (immunosuppressive treatment, e.g. prednisone, monoclonal antibodies anti-inflammatory cytokines). Recent evidence suggests that some immunosuppressive treatments used to control irAE are associated with reduced patient survival. Therefore, it is urgent to define the optimal therapeutic approach to ICI-irAE minimizing its negative impact on cancer outcomes. This will be addressed by this proposal. A team of clinicians and basic scientists with unique expertise in humanized mouse cancer models will develop an unprecedented system to tackle the urgent question that most patients with an ICI-irAE have: ‘What is the optimal way to treat ICI-irAE?’.	Ines Colmegna Logan Walsh

Seed Fund Grant Title

Lead PIs

Humanized Mouse Models to Untangle Mechanisms of Immune Checkpoint
Inhibitors- Immune Related Adverse Events and Effects of their treatment in Tumor Biology

Lay Summary

The concept of treating cancer through the activation of the patient’s own immune system to kill tumor cells led to the development of immune checkpoint inhibitors (ICI). These drugs revolutionized the field of oncology as they control cancers with otherwise very poor prognosis. However, as a consequence of immune activation, up to 50% of cancer patients treated with ICI develop immune related adverse events (irAE, e.g. inflammation of the colon, lungs, joints). The severity of these irAE often requires the use of drugs to control the damage associated with excessive immune activation (immunosuppressive treatment, e.g. prednisone, monoclonal antibodies anti-inflammatory cytokines). Recent evidence suggests that some immunosuppressive treatments used to control irAE are associated with reduced patient survival. Therefore, it is urgent to define the optimal therapeutic approach to ICI-irAE minimizing its negative impact on cancer outcomes. This will be addressed by this proposal. A team of clinicians and basic scientists with unique expertise in humanized mouse cancer models will develop an unprecedented system to tackle the urgent question that most patients with an ICI-irAE have: ‘What is the optimal way to treat ICI-irAE?’.

Ines Colmegna

Logan Walsh

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McGill Interdisciplinary Initiative in Infection and Immunity (MI4)