Control of Cholesterol Metabolism --Bile Acid Transport

描述（由申请方提供）：这些研究的主要目的是进一步了解调节胆固醇穿过质膜和穿过中枢神经系统血脑屏障的过程。这些研究与临床医学的两个广泛领域直接相关：神经退行性变和痴呆的机制以及动脉粥样硬化的形成。一般来说，所有这些研究都将使用各种敲除小鼠进行，这些小鼠缺乏一种或多种固醇运动的关键蛋白质。将测量胆固醇穿过各种组织质膜或穿过血脑屏障的绝对速率，并评估神经功能和肝功能。第一组实验将研究apoE、ABCA 1、SR-BI和LDLR在胆固醇在CMS和血浆之间移动中的可能作用。第二组实验将检验胆固醇和神经节苷脂积累导致NPC 1突变小鼠神经变性的假设。第三组研究将探索可能改变脑中神经元死亡率并改善C型尼曼匹克病中神经功能障碍的各种药物。患有NPC疾病的小鼠（和儿童）也会出现严重的肝脏异常。第四组研究将探索新的药物制剂，中断胆固醇的肠肝循环，并可能防止这种肝细胞死亡。蛋白质ABCA 1在每个器官中普遍表达，包括中枢神经系统，但其促进胆固醇转运的确切功能尚不清楚。在第五组研究中，将在该蛋白缺失或过度表达的条件下测量每个器官中的绝对胆固醇通量率。第六组研究将检查NPC 1 L1，ACAT-2和ABCA 1在调节胆固醇通过肠肝循环流动，从而调节LDL-C水平方面的关系。最后，研究也计划探索胆汁酸合成的替代途径的分子调控是由甾醇27-羟化酶启动。从这些研究中获得的信息，有可能开发新的治疗方法来预防痴呆症（如阿尔茨海默病）的神经变性，并预防动脉粥样硬化和急性冠状动脉闭塞等疾病。

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.