Molecular Basis of Cholesterol Metabolism

描述（由申请人提供）：该计划项目资助（PPG）始于35年前，当时我们描述了控制胆固醇代谢的LDL受体途径，并表明LDL受体缺陷会导致家族性高胆固醇血症和动脉粥样硬化。35年后，我们的目标扩大了，参与者也增加了，但重点仍然是一样的：了解脂质和脂蛋白代谢调节的遗传和分子基础，并利用这些知识来预防和治疗脂质相关疾病，即动脉粥样硬化和代谢综合征。在过去的5年中，我们发表了164篇论文，报告了以下主要进展：1)发现Scap是膜胆固醇的传感受体，控制SREBP加工，从而决定LDL受体数量和血浆LDL水平；2)发现PCSK9突变可降低血浆LDL并减少心脏病发作高达88%；3)证明PCSK9在细胞外结合和降解LDL受体，这一观察结果刺激制药公司开发阻断PCSK9和降低LDL的抗体；4)阐明了溶酶体输出低密度脂蛋白衍生胆固醇的疏水切换机制；5)描述胆固醇调控、泛素介导的HMG辅酶a还原酶和lnsig-1降解途径；6)发现了将辛酸附着在胃饥饿素上的共价修饰酶GOAT，这是胃饥饿素控制食欲和血糖的活性所必需的；7)鉴定了一种激活肝脏脂肪酸合成的蛋白质MIG12；8)发现25-羟基胆固醇作为一种连接先天免疫系统和适应性免疫系统的免疫调节固醇；9)阐明LRP1介导的保护血管平滑肌细胞免受动脉粥样硬化的信号通路。我们现在申请为期5年的续期（36-40年），通过综合的多学科方法进一步研究这些和相关现象。我们建议更多地了解已知分子，并发现与疾病有关的调节脂质和脂蛋白代谢的新分子。我们将继续从分子（即基因、mRNA、蛋白质）、细胞、实验动物和人类患者等各个层面研究这些过程。我们将采用多种方法-生物化学，分子生物学，遗传学，细胞生物学，基因操纵小鼠，动物生理学，临床遗传学和基因组学。只有通过PPG的持续支持，这种综合的跨学科方法才有可能实现。

DESCRIPTION (provided by applicant): This Program Project Grant (PPG) began 35 years ago when we delineated the LDL receptor pathway for control of cholesterol metabolism and showed that defects in the LDL receptor produce Familial Hypercholesterolemia and atherosclerosis. After 35 years, our goals have broadened and the participants have increased, but the focus remains the same: to understand the genetic and molecular basis for regulation of lipid and lipoprotein metabolism and to use this knowledge to prevent and treat lipid-related diseases i.e., atherosclerosis and Metabolic Syndrome. During the last 5 years, we published 164 papers, reporting the following major advances: 1) discovery of Scap as the sensing receptor for membrane cholesterol that controls SREBP processing, thereby determining LDL receptor number and plasma LDL level; 2) discovery of mutations in PCSK9 that lower plasma LDL and decrease heart attacks as much as 88%; 3) demonstration that PCSK9 functions extracellularly to bind and degrade LDL receptors, an observation that stimulated pharmaceutical companies to develop antibodies that block PCSK9 and lower LDL; 4) elucidation of the hydrophobic handoff mechanism for export of LDL-derived cholesterol from lysosomes; 5) delineation of the sterol-regulated, ubiquitin-mediated pathway for degradation of HMG CoA reductase and lnsig-1; 6) discovery of GOAT, the enzyme that attaches octanoic acid to ghrelin, a covalent modification required for ghrelin's activity in controlling appetite and blod sugar; 7) identification of a protein, MIG12, that activates fatty acid synthesis in liver; 8) discovery of 25-hydroxycholesterol as an immunoregulatory sterol that links the innate and adaptive immune systems; and 9) elucidation of an LRP1- mediated signaling pathway that protects vascular smooth muscle cells against atherosclerosis. We now apply for a 5-year renewal (Years 36-40) to further study these and related phenomena through an integrated, multidisciplinary approach. We propose to learn more about known molecules and to discover new ones that regulate lipid and lipoprotein metabolism as it relates to disease. We will continue to study these processes at all levels - molecules (i.e., gene, mRNA, protein), cells, experimental animals, and human patients. We will employ multiple approaches - biochemistry, molecular biology, genetics, cell biology, gene-manipulated mice, animal physiology, clinical genetics, and genomics. Such an integrated interdisciplinary approach is possible only through continued support of this PPG.