Regulation of Membrane Lipid Homeostasis

Project Summary The lipid composition of cell membranes controls bilayer permeability and fluidity as well as the folding and activity of integral membrane proteins, which comprise ~30% of the human proteome. Consequently, the lipid composition of membranes is subject to tight homeostatic control. Over the past 60 years, we have learned a tremendous amount about membrane lipid cell biology, largely from model organisms because forward genetics in cultured human cells remained challenging. CRISPR technology now permits a direct examination of these cellular functions in human cells, opening up a new era of mammalian cell genetics. Our MIRA research strategy is to apply mammalian cell genetics to long-standing questions in cell biology, specifically focusing on the regulation of membrane lipid homeostasis. Over the next 5 years, we will use genetics to address two challenges. For Challenge #1, we will identify new regulators of plasma membrane lipid composition. For Challenge #2, we will discover the mechanism of lysosomal fatty acid export by characterizing genes required for the assimilation of low-density lipoprotein (LDL)-derived fatty acids. Overall, these proposed MIRA studies will make fundamental contributions to the fields of membrane biology, intracellular lipid transport, LDL receptor function/endocytosis, the SREBP pathway, and regulation of lipid synthesis. Given that modulation of cholesterol synthesis and LDL receptor function are primary interventions in the treatment of hypercholesterolemia, these studies may identify new therapeutic targets for the prevention of heart disease, a leading killer of adults in the United States.