Molecular Basis of Cholesterol Metabolism

这项计划项目资助（PPG）始于40年前，当时我们中的两个人（布朗和戈尔茨坦） 描述了控制胆固醇代谢的LDL受体途径，并显示了遗传缺陷如何影响胆固醇代谢。 该受体产生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 扩大了研究范围，增加了研究者数量，但PPG的重点仍然相同，即， 许多疾病是由于代谢失调引起的， 调节脂质代谢将导致预防和治疗常见的脂质相关疾病，包括 动脉粥样硬化和糖尿病并发症。 近年来，我们的PPG团队不断创造出高质量和意想不到的成绩 这些发现开辟了新的研究领域，其中两个包括：1）发现SREBP途径， 是脂质合成和低密度脂蛋白清除的主要调节剂，对疾病的影响范围从 动脉粥样硬化到脂肪肝疾病; 2）发现PCSK 9的LDL降低作用以及功能丧失如何影响 PCSK 9突变导致血浆LDL终生降低，几乎完全保护 冠状动脉疾病-这一发现刺激了两种FDA批准的抗PCSK 9的开发 用于治疗严重高胆固醇血症的单克隆抗体。除了这些发现，该团队 在PPG的支持下，已经产生了400多个独特的cDNA克隆、单克隆抗体、突变细胞 品系和基因工程小鼠，所有这些都是提供给科学界的“没有任何条件 附件” 我们现在申请为期5年的续约（41-45年），以更深入地探索生物化学， 几种蛋白质的生理学，其调节作用对脂质代谢和人类疾病至关重要， SREBP及其调节剂Scap和Insigs; HMG-CoA还原酶及其两种调节剂UBIAD 1和 PPD 1; ACC（乙酰辅酶A羧化酶），脂肪酸合成中的关键酶; UBXD 8， 不饱和脂肪酸;和ANGPTL 3和ANGPTL 8，甘油三酯清除的两种调节剂。我们将探讨 这些蛋白质的调节作用，通过综合跨学科的方法，涵盖了整个 一系列生物学，包括基因、mRNA、细胞、实验动物和人类受试者。如果过去预测 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-项目总结

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