Grant: Foundation Grant

Atg Proteins; Autophagosome; Macroautophagy; Membrane Remodeling; Protein Kinase; Selective Autophagy; Signal Transduction; Structural Biology; Transcriptional Regulation; Transmission Electron Microscopy

<html> <body> <p>Neurodegenerative diseases (ND) are the leading causes of disability in Canada with related health care spending costs exceeding $8B/year. Impairment in the autophagy degradation system has been shown to cause toxic accumulation of protein aggregates commonly found in ND. In this research program, we will use state-of-the-art structure-function methods to investigate the mechanisms of action of the regulatory modules of the autophagy system. We hypothesize that gaining a structural perspective of these modules will clarify the elusive molecular mechanisms of autophagy regulation, and will identify effective strategies to stop autophagy defects in ND. This program tackles 3 major aspects of autophagy regulation:</p> <p> <strong>Theme 1</strong>: <strong>Autophagy signaling module.</strong> The main focus will be the Atg1/ULK kinase, which forms a multi-protein signaling hub that serves as the main &ldquo;on/off&rdquo; switch of the autophagy system. In the short term, our study will shed light on how the activity of the Atg1/ULK signaling complex is being controlled by post-translational modifications. The Atg1/ULK complex is recognized as a <em>bona fide</em> drug target. This work will, in the long term, provide a molecular framework for developing novel autophagy modulators in partnership with the Centre for Drug Research and Discovery (CDRD).</p> <p> <strong>Theme 2: Autophagy cargo selection module.</strong> The main focus will be the autophagy cargo receptor protein p62. Our study will provide crucial insights on the mechanisms through which autophagy cargo receptors recognize and target substrates for sequestration and elimination. Knowledge gained from this work will set the stage for future studies to determine how the substrate selection process is abrogated in ND.</p> <p> <strong>Theme 3: Autophagy transcriptional regulation module.</strong> The main focus will be the Rpd3L histone deacetylase (HDAC) complex that was recently shown to repress expression of <em>ATG</em> (autophagy related) genes. This study will uncover how Rpd3L is targeted to <em>ATG</em> genes and how the activity of the Rpd3 catalytic component is regulated, and will establish a molecular blueprint for developing more specific HDAC inhibitors for autophagy-targeted therapies.</p> <p> <br> <strong>Core Expertise</strong>: This research program is based on our recognized expertise in structure-function analysis of dynamic proteins and multi-protein complexes. In terms of Program Experts, my long term research collaborator Dr. Klionsky (U Michigan) will provide complementary expertise in cell biology analysis, while leading proteomics researchers Dr. Foster (UBC) and Dr. Dong (NIBS, Beijing) will offer technical assistance in mass spectroscopy technologies. Dr. Roberge (UBC, CDRD) will provide crucial support in drug screening and development as the research progresses towards the translation phase.<br> </p> <p> <br> <strong>Mentorship/Training Program</strong>: This program offers exceptional opportunities for trainees to engage in research at the frontiers of the structural biology and autophagy fields and at the interface between basic science and translational medicine, as well as to interact with leading researchers locally and internationally. Through gaining extensive experience in cutting edge techniques such as single-particle electron microscopy (EM) and essential professional skills such as project management and scientific communication, our trainees will be highly sought after in academia and industrial sectors, as well as in scientific communications, or patent law.</p> </body> </html>