Molecular Basis of Cholesterol Metabolism

描述(申请人提供)：该计划项目拨款(PPG)始于35年前，当时我们描述了控制胆固醇代谢的低密度脂蛋白受体途径，并表明低密度脂蛋白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，参与者增加了，但重点仍然是相同的：了解调节脂类和脂蛋白代谢的遗传和分子基础，并利用这些知识预防和治疗与脂类相关的疾病，即动脉粥样硬化和代谢综合征。在过去的5年里，我们发表了164篇论文，报道了以下主要进展：1)发现SCAP作为膜胆固醇的敏感受体，控制SREBP的加工，从而确定低密度脂蛋白受体的数量和血浆低密度脂蛋白水平；2)发现PCSK9突变，降低血浆低密度脂蛋白和心脏病发作多达88%；3)证明PCSK9具有细胞外结合和降解低密度脂蛋白受体的功能，这一观察刺激制药公司开发阻断PCSK9和降低低密度脂蛋白的抗体；4)阐明从溶酶体输出低密度脂蛋白衍生的胆固醇的疏水传递机制；5)描述了类固醇调节、泛素介导的降解HMG CoA还原酶和lnsig-1的途径；6)发现了山羊，这种酶将辛酸连接到Ghrelin上，这是Ghrelin控制食欲和血糖所需的共价修饰；7)鉴定了一种激活肝脏脂肪酸合成的蛋白质MIG12；8)发现了25-羟基胆固醇，它是一种连接天然免疫系统和获得性免疫系统的免疫调节类固醇；以及9)阐明了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年的续展(36-40年)，以通过综合的、多学科的方法进一步研究这些现象和相关现象。我们建议更多地了解已知的分子，并发现与疾病相关的调节脂类和脂蛋白代谢的新分子。我们将继续在所有层面上研究这些过程--分子(即基因、信使核糖核酸、蛋白质)、细胞、实验动物和人类患者。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、基因操纵的小鼠、动物生理学、临床遗传学和基因组学。只有通过继续支持这一项目小组，才有可能采取这种跨学科的综合办法。

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.