Grant: Foundation Grant

Apoptosis; Bcl-2 Family Proteins; Chemotherapy Of Cancer; Fluorescence Lifetime Imaging; Fluorescence Microscopy; Fluorescence Spectroscopy; Protein Protein Interactions; Subcellular Localization; Tail-Anchor Proteins; Therapeutic Development

<html> <body> <p> <strong>The overarching direction of our research program</strong> is developing a comprehensive understanding of the molecular mechanisms and functional consequences of interactions of proteins with a C-terminal Membrane Binding Domain (MBD) with subcellular membranes. Our goal is to identify and validate new potential therapeutic targets. <strong>The 3 major issues we will address are</strong> <strong>1)</strong> the role of membrane binding and protein-protein interactions in the regulation of programmed cell death (apoptosis) by Bcl-2 family proteins in response to chemotherapy (Fig.1A). <strong>2)</strong> the Identification of putative therapeutic targets and characterizing small molecule probes to validate these targets (Figs.2-9) and <strong>3)</strong> the rules governing the targeting signals that specify the subcellular localization of proteins with C-terminal MBDs (Fig.1B &amp; 11) and identifying the cellular machinery that mediates their correct subcellular localization (Fig.12).</p> <p> <br> <strong>Our discovery research is advancing knowledge in two ways:</strong> <strong>1)</strong> by providing a quantitative model for regulation of apoptosis by Bcl-2 proteins with predictive value and <strong>2)</strong> by elucidating the molecular mechanisms by which proteins with C-terminal MBDs are targeted to subcellular organelles. <strong>Our translational research is advancing knowledge</strong> by providing new tools and methods to study protein-protein interactions and the responses of cells to drugs. By validating novel targets for the selective eradication of cancer cells and separate targets for blocking cell death to aid in cell based therapies we are opening new vistas for drug development. By also demonstrating that these targets are druggable <strong>we are optimizing knowledge transfer</strong> within the scientific enterprise and to pharma companies. <strong>Our research is advancing health outcomes</strong> as the new drugs we have worked on enter clinical trials. An intermediate goal of our program is applying the techniques we are developing for precision or even personalized medicine. In the longer term our identification and validation of novel drug targets will further improve patient outcome for both cancer patients and those with degenerative diseases.<br> </p> <p> <strong>The core expertise assembled</strong> is comprised a committed international cadre of physicists, optics engineers, experts in the development of mathematical models of biological processes, bioinformaticians, drug development experts, translational scientists and clinicians with expertise ranging from discovery to clinical trials research.<br> </p> <p> <strong>Mentoring</strong> is highly personalized to the needs of individual trainees through co-supervision and opportunities for full collaboration including internship in industry and opportunities to work directly with front line cancer physicians. Co-supervision provides unique opportunities for our trainees to work in collaborators laboratories including Harvard and research institutes in Europe, currently Ireland and Germany. Moreover, our approach provides unparalleled opportunities for interdisciplinary research in the greater Toronto area.<br> </p> <p>Because the Bcl-2 family proteins constitutes a unique and complete system it has afforded us the opportunity to successfully elucidate the roles of membrane binding, and protein-protein interactions in integrating cellular signals towards crucial life or death decisions for the cell. As a result we now understand the molecular regulation of programmed cell death in response to chemotherapy sufficiently that we are now poised to apply our new knowledge to improve the health of Canadians.</p> </body> </html>