Molecular Basis of Cholesterol Metabolism

这项计划项目赠款(PPG)始于40年前，当时我们两个(布朗和戈尔茨坦) 描绘了控制胆固醇代谢的低密度脂蛋白受体途径，并展示了遗传缺陷是如何 该受体会导致家族性高胆固醇血症和动脉粥样硬化。在接下来的几年里，我们的目标 扩大了调查范围，增加了调查人员，但这次PPG的重点不变， 许多疾病都是由于新陈代谢的失调引起的，而对 调节脂类代谢将导致预防和治疗常见的脂类相关疾病，包括 动脉粥样硬化和糖尿病并发症。 近年来，我们的PPG团队不断产生高质量和意想不到的结果 开辟了新的研究领域，其中两个包括：1)发现了SREBP途径AS 脂类合成和低密度脂蛋白清除的主要调节者，对疾病的影响范围从 动脉粥样硬化到脂肪性肝病；2)PCSK9降低低密度脂蛋白作用的发现和功能丧失 PCSK9基因突变导致血浆低密度脂蛋白终生降低，几乎完全保护了 冠状动脉疾病--这一发现刺激了FDA批准的两种抗PCSK9抗体的开发 用于治疗严重高胆固醇血症的单抗。除了这些发现外，该团队 在此支持下，PPG已经产生了400多个独特的cDNA克隆、单抗、突变细胞 品系和转基因小鼠，所有这些都是向科学界提供的，没有任何线索 附在一起的。“ 我们现在申请5年的续期(41-45年)，以更深入地探讨生物化学和 几种蛋白质的生理学，这些蛋白质的调节作用是脂代谢和人类疾病的核心- SREBPs及其监管机构SCAP和Insigs；HMG-CoA还原酶及其两个监管机构UBIAD1和 PPD1；ACCS(乙酰辅酶A羧基酶)，脂肪酸合成的关键酶；UBXD8，脂肪酸合成的调节因子 不饱和脂肪酸；以及两种甘油三酯清除调节剂Angptl3和ANGPTL8。我们将探索 通过涵盖整体的综合跨学科方法对这些蛋白质的调节作用 生物学的范围，包括基因、mRNA、细胞、实验动物和人类受试者。如果过去的预测 在未来，我们将继续做出对人类健康有直接影响的发现。 C/PPG 2015-总体-项目摘要

This Program Project Grant (PPG) began 40 years ago when two of us (Brown and Goldstein) delineated the LDL receptor pathway for control of cholesterol metabolism and showed how genetic defects in the receptor produce Familial Hypercholesterolemia and atherosclerosis. Over the ensuing years, our goals broadened and the number of investigators increased, but the focus of this PPG remains the same, namely, that many diseases result from misregulation of metabolism and that understanding the molecular basis for regulation of lipid metabolism will lead to prevention and therapy of common lipid-related disorders, including atherosclerosis and the complications of diabetes. In recent years, our PPG team has continued to produce high quality and unexpected results that have opened new fields of investigation, two of which include: 1) discovery of the SREBP pathway as a master regulator of lipid synthesis and LDL clearance, with implications for diseases ranging from atherosclerosis to fatty liver disease; 2) discovery of the LDL-lowering action of PCSK9 and how loss-of-function mutations in PCSK9 produce life-long reductions in plasma LDL and almost complete protection against coronary artery disease – a discovery that stimulated development of two FDA-approved anti-PCSK9 monoclonal antibodies for treatment of severe hypercholesterolemia. In addition to these discoveries, the team supported by this PPG has generated more than 400 unique cDNA clones, monoclonal antibodies, mutant cell lines, and genetically engineered mice, all of which are provided to the scientific community with “no strings attached.” We now apply for a 5-year renewal (Years 41-45) to probe more deeply into the biochemistry and physiology of several proteins whose regulatory actions are central to lipid metabolism and human disease – SREBPs and their regulators, Scap and Insigs; HMG-CoA reductase and two of its regulators, UBIAD1 and PPD1; ACCs (acetyl-CoA carboxylases), key enzymes in fatty acid synthesis; UBXD8, a regulator of unsaturated fatty acids; and ANGPTL3 and ANGPTL8, two regulators of triglyceride clearance. We will explore the regulatory actions of these proteins through integrated interdisciplinary approaches covering the whole range of biology, including genes, mRNAs, cells, experimental animals, and human subjects. If the past predicts the future, we will continue to make discoveries that have direct implications for human health. C/PPG 2015 – Overall - Project Summary