Role of lysosomes in homeostasis and disease

Mentor: Abhinav Diwan, MD, Professor, Department of Medicine, Cardiovascular Division

Lab description: The Diwan lab is investigating the regulation of lysosome function in physiology and disease. Their program has discovered evidence for acquired lysosome dysfunction in cardiac myocytes and macrophages in the setting of myocardial infarction and cardiomyopathies and in protein aggregate induced cardiomyopathy and heart failure. His lab employs molecular, genetic, and surgical modeling techniques in animal models to investigate lysosome biology in cardiac stress and homeostasis using basic research approaches.

Projects: Specific research projects in the Diwan lab that will offer interdisciplinary training opportunities for undergraduate students are as follows. Project 1: The first project focuses on elucidating the role of specific genes (n=6) uncovered in a genetic screen of starvation survival in lysosome biogenesis transcription factor-deficient worms in regulating the starvation response in worms and mammalian cells. Students will test the role of individuals genes in mutant worm lines and cells targeted for loss of function of these genetic pathways to evaluate their role in starvation stress. Project 2: will focus on uncovering the redundancy of three members of the lysosome biogenesis transcription factor family, namely TFEB, TFE3, and Mitf, in genetically targeted murine embryonic fibroblasts. These data will be correlated with murine models with cardiac myocyte-specific deficiency of these transcription factors to understand their role in cardiac homeostasis. Project 3: is to evaluate the role of genetic mutations and stress-induced post-translational modifications in CRYAB, a cardiac enriched chaperone protein, in causing aberrant phase separation and protein aggregation, leading to proteotoxic cardiomyopathy. The undergraduates will work with targeted phase separation assays, as well as generic tool compounds to disrupt phase separation to assess the mechanisms whereby CRYAB becomes aggregate-prone. Project 4: A fourth project is focused on zinc-induced lysosomal remodeling in worms and mammalian cells. This is based on preliminary observations that toxic metals are sequestered within lysosomes to attenuate cellular toxicity. Students will evaluate worm models of gain and loss of function of the lysosome biogenesis program and quantify metals in the lysosomal compartment using state-of-the-art organelle isolation strategies and mass spectroscopy-based chemical assays.