Grant: Discovery Grants Program - Individual

Autophagy is a degradative cellular program that is upregulated by a wide variety of stresses. Nutrient stress can induce a generalized degradation of cytosol to balance energy, while organelle-specific damage can lead to targeted autophagic clearance. When autophagy is directed towards a specific target we call this selective autophagy. Research into the mechanisms of selective autophagy is largely focused on organelle specific autophagy receptors, which act as a bridge linking the organelle to the autophagosome. However, it remains very poorly understood how selective autophagy is initiated upstream of these receptors and other autophagy proteins. Our previous work on bacterial stress (Losier et al Cell Reports 2019) uncovered distinct autophagy regulatory pathways for the selective autophagy of bacteria. This led us to undertake a systematic analysis of the cellular signaling that directs selective autophagy. NSERC funded trainees Cloe Losier and Karyn King performed screens CRISPR/Cas9 and siRNA screens to uncover the signaling that regulates the selective autophagic degradation of portions of: the nucleus, peroxisomes, endoplasmic reticulum, or endosomes and lysosomes. These screens have been completed and found preliminary signaling networks for each type of autophagy as well as some newly described regulators that were common for 2 or more stressors, suggesting common regulatory pathways may link certain subtypes of autophagy. My research focus in the last 17 years centers around understanding the essential signaling pathways responsible for maintaining cellular homeostasis under stress. Our long-term goal for this research program is to characterize the signaling pathways that regulate autophagy in a systematic and stress-specific manner to comprehensively fill critical knowledge gaps in how cells utilize autophagy to mitigate cell stress. Our 5-year goals for this research program are to validate and characterize our discovery of the signaling networks that regulate selective autophagy. Additionally, we will characterize newly discovered crosstalk from our screen that functional link different types of selective autophagy. These analyses will significantly improve our fundamental understanding of how autophagy is regulated and directed to specific cargo. This work will be performed by 3 PhD students, 2 COOP students and 2 honours students who will receive training in cutting-edge and in demand technologies and concepts including: genome editing, next-generation sequencing, bioinformatics and data analysis, and molecular biology. This training will be supported by my lab and the Core facility I direct and collaborators giving the trainees a diverse training environment. Students will also receive training in communications and EDI and be encouraged to join the scientific outreach performed by our laboratory. Collectively, the trainees from this grant will enter the workforce with skillsets that are extremely valuable to Canada.