The long term goal of this research is to understand how cholesterol gains access to intracellular compartments for utilization, storage and cellular regulation, via two glycoproteins: NPC1 and LAMP proteins. NPC1 is needed for the egress of endocytosed, LDL-derived cholesterol from lysosomes into the cytoplasm. LAMP proteins constitute the major glycoproteins that line the limiting membranes of lysosomes. The goal of this application is to study how these proteins may cooperate to transport cholesterol out of lysosomes, using biochemical and cell biological approaches. Experiments are proposed to investigate further, the cholesterol-dependent interaction between these proteins, and how they, and their interactions, may influence downstream activation of lysosome biogenesis. These experiments will provide important information regarding how cells may sense and signal the availability of cholesterol in lysosomes, and export cholesterol from lysosomes. This work has important implications for a number of disease states including cardiovascular disease, cancer, and neurological disorders.
Cholesterol is an essential component of cellular membranes, yet increased plasma cholesterol is a major risk factor for atherosclerotic cardiovascular disease. This application seeks to study two proteins, NPC1, a protein of lysosomes that is needed for the delivery of LDL-derived cholesterol into the cytoplasm, and LAMP proteins, the major glycoproteins of the lysosome. The goal is to understand how these proteins cooperate in the process of cholesterol export from lysosomes. This process is essential for normal cell function and important for our understanding of cardiovascular disease, cancer and neurological disorders. NPC1 is also needed for Ebola virus entry, so understanding its function may provide important clues toward blocking a deadly viral pathogen.
