Control of Cholesterol Metabolism --Bile Acid Transport

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DESCRIPTION (provided by the applicant): The broad objective of these studies is to further understand the processes that regulate cholesterol movement across plasma membranes and across the blood brain barrier of the central nervous system. These studies have direct relevance to two broad areas of clinical medicine: the mechanisms of neurodegeneration and dementia and the formation of atherosclerosis. In general, all of these studies will be undertaken using a variety of knockout mice that lack one or more critical proteins for sterol movement. Absolute rates of cholesterol flux across the plasma membranes of various tissues or across the blood brain barrier will be measured and neurological and hepatic function will be assessed. The first set of experiments will investigate the possible role of apoE, ABCA1, SR-BI and LDLR in the movement of cholesterol between the CMS and the plasma. A second set of experiments will test the hypothesis that cholesterol and ganglioside accumulation leads to neurodegeneration in mice with a mutation in NPC1. A third set of studies will explore various agents that might alter the rate of neuron death in the brain and ameliorate the neurological dysfunction seen in Niemann-Pick type C disease. Mice (and children) with NPC disease also develop serious liver abnormalities. A fourth group of studies will explore new pharmaceutical agents that interrupt the enterohepatic circulation of cholesterol and might prevent such liver cell death. The protein ABCA1 is expressed ubiquitously in every organ, including the central nervous system but its exact function in promoting cholesterol transport is unknown. In a fifth set of studies, absolute cholesterol flux rates will be measured in every organ under conditions where this protein is either deleted or over expressed. A sixth set of studies will examine the relationship between NPC1L1, ACAT-2 and ABCA1 in regulating cholesterol flow through the enterohepatic circulation and, hence, the level of LDL-C. Finally, studies are also planned to explore the molecular regulation of the alternative pathway for bile acid synthesis that is initiated by sterol 27-hydroxylase. With the information gained from these studies, it is possible that new therapies can be developed to prevent neurodegeneration with dementias such as Alzheimer's disease, and to prevent atherosclerosis and diseases such as acute coronary occlusion.