Cellular cholesterol movement and homeostasis

性状（由申请方提供）：质膜磷脂与胆固醇形成化学计量复合物。超过磷脂结合能力的过量胆固醇产生具有高化学活性的胆固醇的新池。这种高活性胆固醇然后作为稳态信号;例如，通过调节细胞胆固醇平衡和线粒体氧固醇生物合成的内质网效应器。目前的建议将考虑两个额外的和未开发的监管作用的活性质膜胆固醇，即，在线粒体类固醇生成和质膜胆固醇转移到循环高密度脂蛋白的清道夫受体SR-BI和ABCA 1转运。对全身麻醉的神秘分子机制也提出了一个新的假说。我们认为，大范围的麻醉剂的行为插入到质膜双层的神经元，取代，从而激活一小部分的胆固醇。这些活跃的胆固醇会扰乱神经元的离子通道，导致麻醉。这一假设将通过检查激活胆固醇的两亲分子库对离子通道活性的影响来检验。还将测试胆固醇本身和胆固醇络合磷脂对离子通道活性的影响。我们注意到许多质膜蛋白的功能依赖于胆固醇或受胆固醇的影响。这些现象与胆固醇驱动的横向相分离（即，木筏编队）是强大的，但有争议的。因此，我们将表征不同的水溶性插层的两性分子探针，可以增加，减少或以其他方式扰乱推定的质膜筏的形成，允许他们的分析和操纵。这些探针通过与双层磷脂复合、置换和取代其胆固醇以改变侧向相分配的驱动力来起作用。插层的两性通道，调节筏/微区的形成和行为可能有基本的科学和治疗效用。这些研究将测试关于活性胆固醇生理学的新假设。它们将极大地增加我们对这一重要膜组分的基本理解，影响各种重要的医学问题，如心血管疾病，由筏包埋蛋白介导的（病理）生理过程和临床麻醉。公共卫生相关性：由于动脉粥样硬化性心血管疾病对健康造成的巨大负担，细胞胆固醇受到普遍关注。人们普遍认为，动脉粥样硬化应被理解为正常的生理过程出错，需要深入了解真核细胞固有的基本固醇管理系统。阐明膜胆固醇复合物和胆固醇活性的生理学和实际意义将有望在胆固醇相关疾病的治疗和预防方法的发展中发挥作用。.

DESCRIPTION (provided by applicant): Plasma membrane phospholipids form stoichiometric complexes with cholesterol. Excess cholesterol beyond the binding capacity of the phospholipids creates a novel pool of cholesterol with a high chemical activity. This high-activity cholesterol then serves as a homeostatic signal; for example, by regulating endoplasmic reticulum effectors of cell cholesterol balance and mitochondrial oxysterol biosynthesis. The present proposal will consider two additional and unexplored regulatory roles for active plasma membrane cholesterol; namely, in mitochondrial steroidogenesis and in the transfer of plasma membrane cholesterol to circulating high density lipoproteins by the scavenger receptor SR-BI and the ABCA1 transporter. A novel hypothesis for the mysterious molecular mechanism of general anesthesia is also proposed. We suggest that a wide range of anesthetics act by intercalating into the plasma membrane bilayer of neurons, displacing and thereby activating a small fraction of their cholesterol. This pool of active cholesterol would then perturb neuronal ion channels, leading to anesthesia. This hypothesis will be tested by examining the influence on ion channel activity of a library of amphipaths that activate cholesterol. The effects of cholesterol itself and of cholesterol-complexing phospholipids on ion channel activity will also be tested. We note that the function of numerous plasma membrane proteins is dependent on or otherwise influenced by cholesterol. The premise that these phenomena are related to cholesterol-driven lateral phase separation (i.e., raft formation) is powerful but controversial. We shall therefore characterize diverse water-soluble intercalating amphipaths as probes that can increase, decrease or otherwise perturb the formation of putative plasma membrane rafts, allowing for both their analysis and manipulation. These probes act by complexing with bilayer phospholipids, displacing and substituting for their cholesterol so as to alter the driving force for lateral phase partition. Intercalated amphipaths that modulate raft/microdomain formation and behavior could have basic scientific and perhaps therapeutic utility. These studies will test new hypotheses about the physiology of active cholesterol. They will greatly increase our fundamental understanding of this essential membrane component, bearing on varied and important medical issues, such as cardiovascular disease, (patho)physiological processes mediated by raft-embedded proteins and clinical anesthesia. PUBLIC HEALTH RELEVANCE: Cell cholesterol is of universal interest and concern because of the enormous burden on health imposed by atherosclerotic cardiovascular disease. It is widely appreciated that atherogenesis is to be understood as normal physiological processes gone awry and that insights are needed into the basic sterol management systems inherent in eukaryotic cells. Elucidating the physiology and practical implications of membrane cholesterol complexes and cholesterol activity will hopefully play a role in the development of therapeutic and preventive approaches to cholesterol-related diseases. .