Our goal is to understand the machinery that maintains the constancy of cholesterol in cell membranes. We expect to discover new proteins and biochemical processes that control the production, intracellular transport, and storage of cholesterol. These discoveries will serve as a model that permits other scientists to expose related mechanisms that control the membrane content of other lipids that are essential for normal cell function. Defects in these control processes will likely be found to underlie diseases as diverse as atherosclerosis, neurodegeneration, and cancer. Cell membranes are fundamental to life, and defects in their function underlie many diseases. Membranes of different organelles have different lipid compositions. For example, cholesterol is markedly enriched in the plasma membrane compared with the ER. Scientists know the enzymes that synthesize and degrade the various lipids in different cell membranes. Yet, very little is known about how these enzymes are regulated so as to maintain differential lipid compositions. Our laboratory made the initial inroad into this problem through the discovery of the SREBP family of transcription factors that control synthesis and uptake of cholesterol and fatty acids. We discovered four proteins whose actions govern the regulated trafficking mechanism that dictates the activities of SREBPs. We are now in a unique position to decipher precisely how this system works at a molecular level. Our findings will drive the field of membrane biology at the level of fundamental understanding and at the level of disease. In the course of our work, we will continue to invent new methodologies, just as we have in the nearly 40 years since we first invented methods to discover receptor-mediated endocytosis and its specific application to LDL. We will uncover new concepts, just as we did when we defined the general processes of regulated-intramembrane proteolysis in 2000 and hydrophobic handoff in 2009. Our work will help scientists in many fields of biology to understand the membranes that play essential roles in all biologic functions.

Public Health Relevance

Although lipid membranes are essential for all cellular life, it is remarkable that we know very little about how the lipid composition of the membrane is maintained. The studies outlined here will provide direct insight into one mechanism - that which controls membrane cholesterol. Discoveries funded by this Program Project Grant have already exerted considerable impact on biology and medicine. For example, discovery of the LDL receptor taught us how the body controls LDL, the lipoprotein most closely linked to heart attacks. Illustrations of the LDL receptor pathway are standard in most textbooks of biochemistry and cell biology. Discovery of the SREBP pathway taught us the molecular basis for the cholesterol-lowering action of statin drugs, which have extended millions of lives. Moreover, this discovery provided a plausible mechanism for the cholesterol elevating effects of high fat diets;it helped to explain how genetic defects in cholesterol homeostasis can produce a plethora of birth defects in mice, ranging from cleft palate to hairlessness (5;6);and it provided insight into how rapidly growing cells, such as cancer cells, produce the lipids that they require for the synthesis of cell membranes. We discovered the SREBPs only 17 years ago. Already they have been the subject of more than 3000 scientific publications (as revealed by Pub Med). Figures illustrating the SREBP pathway have appeared in three widely used cell biology and biochemistry textbooks: Lodish, et al. Molecular Cell Bioloov. 6'^ ed., pp. 707-709, (2008);Pollard, et al. Cell Bioloov. 2^ ed.. pp. 360-363, (2008);and Stryer's Biochemistry. 6 ed., pp. 742-743 (2007). Further discoveries projected from this Project should continue to have an impact on the science that we teach our students. They will also enhance our understanding and treatment of diseases as diverse as neurodegeneration and cancer as well as atherosclerosis itself.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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