Exploring the Role of Hepatic Lipase and Lipid Metabolism in AMD
MentorVenkata Ramana Murthy Chavali, PhD
The goal of my project is to understand how hepatic lipase and dysregulated lipid metabolism are involved in the pathogenesis of AMD. Hepatic lipase (HL) breaks down HDL to smaller particles, and reduced HL may impair the ability of RPE cells to export cholesterol, leading to increased accumulation of large CE- and apoE-HDL rich particles that could cause drusen formation in AMD. For the first aim, we will study the effects of HL knockout and overexpression on cholesterol efflux using polarized 2D iPSC-RPE cultures. For the second aim, we will characterize the retinal phenotype in an HL/EL dKO mouse model and investigate the development of AMD-like retinal degenerative changes with and without a high-fat diet.
To the best of our knowledge, HDL has not been investigated as a major source of druse lipid, nor has it been suggested in the literature that HDL may contribute to druse deposition in AMD in a substantial manner. Our study will establish if HDL accumulation results in RPE pathology and if modulating HDL results in efflux and accumulated cholesterol clearance. Well-characterized HL/EL dKO mice can be used as a novel model for studying AMD lipid biogenesis. Our study will reveal if modulation of LIPC can alter the mechanisms of cholesterol metabolism in RPE both in vitro and in vivo and if they can be associated with AMD by affecting cholesterol efflux pathways. Our study is not only innovative, but it will also extend the existing knowledge about the accumulation of lipid deposits as drusen deposits which are the primary hallmarks of AMD. They will provide insight into the role, mechanisms, and pathways regulating the cholesterol biogenesis in the aging retina and ways to intervene in this step for positive therapeutic application.