Research laboratories:
Department of Pharmacology and Therapeutics,
Faculty of Medicine and Health Sciences, McGill University,
3655 Promenade Sir William Osler,
Montreal, Canada H3G 1Y6
Professor Dusica Maysinger's areas of expertise include the mechanisms of drug actions and signaling mechanisms in cell survival and differentiation. Her ongoing studies address a number of essential questions relevant to cell survival and processes leading to cell death, differentiation or survival. Dissection of signal transduction pathways involved in these processes in different cell types including brain cells has been a long-term interest of her laboratory. Her earlier interdisciplinary studies with several collaborators showed that: (1) Islets are dying in a post isolation period by apoptosis and delayed necrosis, (2) An early pharmacological intervention during the isolation can enhance the islet survival, (3) Combined therapeutic intervention during and after the isolation as well as during the post-transplantation period is beneficial, and (4) Induction of islet neogenesis is a promising new direction to medical intervention in diabetes.
Complementary to these molecular biological and mechanistic studies are investigations of the nano-delivery systems and other drug and cell-delivery systems to promote cell survival in vitro and in vivo. A special aspect of these studies is the combination therapies with combined drug delivery systems to achieve local drug release, promote three-dimensional environment to neural cells.
More recently, most of Prof. Maysinger’s research activities have focused on problems in neurodegenerative processes and the underlying mechanisms associated with them. Considering the growing importance of nanotechnological products, her research focuses on nanostructure effects on brain cells, specifically glia. Her lab has been at the forefront of investigating polymeric and metallic nanoparticles and nanoclusters in neural cells under both physiological and pathological conditions. These studies include three main subgroups:
1. Metallic nanostructures for imaging and interactions with cell organelles
They tested different nanomaterials and probes for applications in vitro and in vivo in animal models of diseases. aiming for safer, quantitative sensors for a wide range of applications. The most interesting findings came from investigations of gold nanoparticles, revealing their shape, size and surface ligand effects. They show that these effects are associated with organellar responses involving endosomes, lysosomes, endoplasmic reticulum, lipid droplets, mitochondria and the cytoskeleton.
Gold nanocluster (AuNC) structures with 25 gold atoms and two different ligands (cysteine and glutathione).
2. Dendrimers and their effects on glial cells
Dendrimers, a tree-like nanostructures often exert inherent biological activity including anti-inflammatory effects in neural cells. Dendritic sulfated polyglicerols (dPGS) in brain cells possess anti-inflammatory properties and modulate an interplay between microglia and astrocytes following pro-inflammogen. They also show nanostructure effects in primary human brain cells and complex 3D human brain models (organoids). Their recent studies show interaction sites of nanostructures with cell proteins and interference with protein-protein interactions using proximity ligation assays, complementing molecular modeling.
Cytosolic amount of RAGE-HMGB1 interactions in human microglia treated with dPGS (1 uM) and recombinant human HMGB1 (1 ug/mL) after 24h in serum deprived conditions. The RAGE inhibitor Azeliragon (AZL, 1 uM) was used as control. Proximity ligation assay (PLA) was performed following the Duolink fluorescence-based protocol (Thermo Fisher Scientific). Cells were labelled with Phalloidin 488 (actin) and DAPI (nucleus). The amount of interactions was analyzed in ImageJ.
3. Nanodelivery systems for hydrophilic and lipophilic compounds and proteins
They have tested different types of nanodelivery systems tailored for therapeutic agents of interest (vesicles for hydrophilic compounds, micelles for lipophilic compounds, dendritic nanostructures for both hydrophilic and lipophilic compounds).
Several self-assembly systems were also tested for loading efficiency and release of anticancer and putative senolytic agents (e.g. curcumin, SAHA, quercetin). These agents have low aqueous solubility and stability without nanocarriers. A facile, cost-effective, and environmentally friendly synthesis of nanocarriers together with a thorough testing of their effects in neural and other cell types is necessary before their application in clinics.
Gold nanoclusters (AuNC) interact with cell proteins and their complexes thereby modulating cell morphology andfunctions.