Research

Cell signaling and cell interactions with their local environment and the extracellular matrix (ECM) is essential for the development, differentiation and maintenance of cells, tissues and organs. Faculty whose research falls under this theme use a wide variety of innovative approaches and models, studying receptor tyrosine kinase signaling, cell senescence, cell-ECM dynamics, biomineralization, mitochondrial dynamics, pituitary hormone synthesis, and blood flow in the vasculature, to understand how cells integrate signals in response to physical and chemical interactions. Specific cell and physiological processes downstream of these responses include vesicle trafficking, endosome maturation, cell adhesion, migration, morphology, and growth, as well as cellular transitions in metabolic profiles, cell cycle, immune pathway and cell death. This research in this theme is directly relevant to human disease. Genetic mutations in the genes encoding ECM components lead to debilitating defects in blood vessels, bone and skin, while abnormal deposition of minerals in soft tissues such as the kidney and blood vessels lead to various pathologic conditions including urolithiasis and atherosclerosis. Defects in numerous signaling pathways occur in cancer and neurodegenerative diseases. A basic understanding of cell signaling, cell-environment interactions and cell-ECM dynamics will help to design preventative, diagnostic and therapeutic strategies for the associated disorders.

Cell biologists in this theme use various models (neurons, Chlamydomonas, genetically modified mice and C. elegans) to study the dynamic regulation of cytoskeleton networks such as microtubules that control cell shape and migration and affect cell signaling. Researchers also study the involvement of the cytoskeleton in endocytosis, in chromosome segregation during cytokinesis and the importance of the cytoskeleton for the intracellular transport of vesicles and organelles, such as endosomes, lysosomes and mitochondria. The cytoskeleton forms specialised structures such as cilia and lamellipodia, which play essential roles in the development and function of cells. Understanding the basic cell biology of microtubule dynamics, cilia assembly and function, cytokinesis, and the regulation of vesicle and organelle dynamics and intracellular trafficking is critical to advance treatment options for diseases resulting from defects in these processes, including lysosomal storage disorders, cilia-related diseases, neurodegenerative diseases, and cancer.

Faculty
Susanne Bechstedt
Khanh Huy Bui
Nathalie Lamarche-Vane
Craig Mandato
Carlos Morales
John Presley

Adjunct Professors
Jean-Francois Côté
Stéphane Lefrancois
Alexei Pchejetski
Michael Sacher

Cryo-electron microscopy is an exciting imaging technique whereby samples are rapidly frozen and kept in a frozen hydrated state during imaging - typically below -165 ºC. The electron microscope can then deliver snapshots of biological samples as they exist, immobilized in ice. By averaging many images of one type sample, a 3-dimensional reconstruction can be generated that describes molecules of interest, such as proteins, or protein complexes, even down to the amino-acid level. New methods of handling this data are needed to answer specific questions. In particular, the sorting of the individual images of proteins can be a complicated affair - we don’t know what the protein looks like, we don’t know how many different states it will adopt, and there is no guarantee all states behave the same way. We are devising new protocols to deal with these problems computationally, and working out ways to acquire data that circumvents some of the difficulties we encounter. The methods we are working on include: single particle analysis, electron tomography and sub-tomogram averaging, and micro-electron diffraction.

Faculty
Huy Bui
Susanne Bechstedt
Joaquin Ortega
Mike Strauss
Shuaiqi Guo

The promise of biomedical research to find treatments for diseases rests in our ability to understand the biology of the cellular processes sustaining life. Major advances are only possible if researchers can directly visualize the enzymes that perform chemical reactions mediating essential cellular processes. The most detailed insights come from atomic structures of macromolecules and complexes involved in these processes in relevant functional states. Faculty whose research falls under this theme seek to understand the fundamental principles governing the structure and mechanism of some of these protein complexes (for example, microtubules, motor proteins, ribosomes, transport proteins and various other enzymes) performing essential roles in bacteria, viruses, and mammalian cells. Solving these structures requires combined approaches and instruments capable of imaging biological specimens at atomic resolution and dissecting their different levels of complexity. Faculty in this theme constitute the largest cluster of cryo-electron microscopy expertise in Canada with researchers working in the areas of single particle cryo-electron microscopy, cryo-electron tomography, correlative light-electron microscopy and computation for the development of image processing tools. These innovative approaches strive to translate the information obtained from cryo-electron microscopy 3D reconstructions of enzymes to understand how they work in their natural environment, the cell. Integration of the structural information at all levels of complexity in living organisms will lead to design principles that can be exploited for synthetic biology and next generation therapeutics. High-resolution structures will also help to elucidate how alterations in these complexes lead to malfunction, causing developmental defects, neurodegenerative disorders, cancer and other diseases.

Faculty
Huy Bui
Susanne Bechstedt
Joaquin Ortega
Dieter Reinhardt
Mike Strauss
Natalie Zeytuni
Shuaiqi Guo