Tuesday, May 14, 2024
5/14/2024
PROJECT SUMMARY/ABSTRACT Alport Syndrome (AS) is a hereditary disease caused by mutations in collagen type IV, a main component of the glomerular basement membrane (GBM). Podocytes are key components of the glomerular filtration barrier, and their interaction with the GBM is crucial to maintain the permeability of this barrier. We have demonstrated that pathogenic renal lipid accumulation occurs in an experimental model of AS and that podocyte lipotoxicity is the key determinant of podocyte injury in other glomerular disease. My preliminary data show that the intracellular triglyceride (TG) content is increased in glomeruli of Col4a3 KO mice, a mouse model for AS as well as in immortalized podocytes which I established from these mice (AS podocytes). Yet, the detailed mechanism by which lipid accumulation contributes to podocyte lipotoxicity in AS remains to be elucidated. The proposed research will explore a novel mechanism linking PLIN5 deficiency to podocyte lipotoxicity. PLIN5 is a protein controls lipolysis and regulates free fatty acid (FFA) flux from lipid droplets (LDs) to mitochondrial by establishing physical contact between these organelles. From my preliminary data, I generated the hypothesis that PLIN5 deficiency in AS causes excessive TG lipolysis and loss of LD-mitochondrial contacts resulting in FFA accumulation and mitochondrial dysfunction. I propose the following specific aims using innovative cell biological, imaging analysis, and mouse model approaches: (SA1) investigate the role of podocyte PLIN5 in recruiting LDs to mitochondria. (SA2) Define the contribution of PLIN5 deficiency to mitochondrial dysfunction and renal failure in AS. I have created a comprehensive career development plan supported by my mentor and co-mentors to (1) ensure my progress and success in carrying out this research proposal and (2) to facilitate my transition to an independent research career focused on lipid metabolism in association with mitochondrial function in Alport Syndrome. This plan includes (1) regular meetings with my mentor, co- mentors, and advisory committee, (national and global academic readers in medicine and science) to provide research and career guidance, (2) research and career development seminars, learning new methodologies of microscopy, mitochondrial function, and lipidomics, and (3) activities for career growth including mentoring, publication, presentation, and application for independent research funding. My mentor and I have also agreed upon a transition plan to distinguish myself from my mentor’s laboratory. My training will be carried out in an unparalleled academic environment at University of Miami, Miller School of Medicine, which provides dedicated career development programs and all necessary research support and supplies through his mentor, co-mentors, and institutional core services. Collectively, this research and career development proposal is a product of my ambition and capacity to transition to an independent research career.
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