New Approaches to Reduce Residual Cardiovascular Risk

降低残余心血管风险的新方法

• 批准号: 10543864
• 负责人: JAY D. HORTON
• 金额: $ 248.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543864
• 关键词: ANGPTL3 gene; Acetyl-CoA Carboxylase; Acyltransferase; Angiopoietins; Animals; Antibody Formation; Apolipoproteins B; Binding; Binding Proteins; Binding Sites; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cholesterol; Clinical; Co-Immunoprecipitations; Collaborations; Complex; Coronary heart disease; Cytosol; DNA Resequencing; Dedications; Development; Eligibility Determination; Endoplasmic Reticulum; Enzymes; Event; Fatty Acids; Fatty-acid synthase; Foundations; Funding; Genes; Genetic study; Goals; High Density Lipoproteins; Hypertriglyceridemia; Individual; Knowledge; LDL Cholesterol Lipoproteins; LIPG gene; Lipids; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Mass Spectrum Analysis; Membrane; Metabolic; Metabolic Pathway; Metabolism; Molecular; Multienzyme Complexes; Mutation; National Heart, Lung, and Blood Institute; Palmitic Acids; Paper; Participant; Pathway interactions; Pharmaceutical Preparations; Physiological; Plasma; Process; Production; Productivity; Program Research Project Grants; Proteins; Public Health; Publishing; Recording of previous events; Research Personnel; Research Project Grants; Residual state; Resolution; Risk; Series; Specificity; Sterols; Therapeutic Intervention; Triglycerides; Variant; Very low density lipoprotein; Work; cardiovascular risk factor; design; epidemiology study; inhibitor; innovation; insight; lipoprotein lipase; loss of function mutation; member; mimetics; novel; novel strategies; novel therapeutics; originality; population based; prevent; small molecule; success; tissue culture; transcription factor

PPG Title: New Approaches to Reduce Residual Cardiovascular Risk SUMMARY/ABSTRACT In the last 40 years, significant progress has been made in reducing cardiovascular events by lowering plasma LDL-cholesterol (LDL-C). While statins and PCSK9 inhibitors effectively decrease LDL-C levels, significant residual risk of CHD remains even in maximally treated individuals with low plasma levels of LDL-C. Epidemiological and genetic studies suggest that a significant proportion of the residual risk is due to elevated plasma levels of triglyceride-rich ApoB-Containing Lipoproteins (ApoBCLs). The three projects that comprise this Program Project Grant (PPG) will elucidate new molecular mechanisms that regulate the synthesis, secretion, and metabolism of ApoBCLs. Our PPG is comprised of distinguished investigators with a longstanding history of collaboration, five of whom (Goldstein, Brown, Hobbs, Horton, and Cohen) have worked together for 25 years. In Project 1 of this new PPG, Radhakrishnan, Brown, and Goldstein have used an original and innovative screening protocol to identify a cholesterol-mimetic small molecule that binds to Scap with high specificity and blocks activation of SREBPs, the transcription factors that activate genes required for the synthesis of cholesterol, fatty acids (FAs), and triglycerides (TGs). This compound will be used to elucidate the molecular mechanism by which Scap senses sterols, enabling the first description of Scap’s cholesterol binding site at atomic resolution. The current cholesterol mimetic compound and more potent derivatives in development will be used to assess the clinical implications of a Scap inhibitor for reduction of plasma ApoBCLs. In Project 2, Horton, Kim, and Liang have identified a new lipogenic enzyme complex in liver. They will characterize components of the FA synthesis complex and determine how this complex interacts with additional FA modifying proteins and acyl-transferases required to synthesize TGs and ApoBCLs. Completion of the proposed studies will identify new opportunities for therapeutic interventions to reduce the synthesis of FAs, TGs, and VLDL. In Project 3, Hobbs and Cohen used population-based resequencing to identify loss-of-function mutations in angiopoietin-like (ANGPTL) 3 and 8. They showed that mutations in either protein result in lower plasma LDL- cholesterol and TG levels. Their studies will elucidate the mechanisms underlying the ApoBCL lowering effects of ANGPTL3 and ANGPTL8. In the process, they will define a new pathway that promotes clearance of ApoBCLs independently of the LDL receptor. The Research Projects will be supported by three Cores: Administrative, Tissue Culture & Antibody Production, and Mass Spectrometry. Members of this PPG have a long record of collaborative interactions and exceptional productivity. We will continue to focus on bold hypotheses designed to answer critical questions. The investigators take special pride in publishing papers that are characterized by originality and scientific rigor. The successful completion of our projects holds great promise for exposing new therapeutic opportunities for the reduction of plasma ApoBCLs and residual cardiovascular risk.

PPG标题：降低残余心血管风险的新方法 摘要/摘要 在过去的40年里，在通过降低血浆浓度来减少心血管事件方面取得了重大进展 低密度脂蛋白-胆固醇(LDL-C)。虽然他汀类药物和PCSK9抑制剂有效地降低了低密度脂蛋白水平，但显著 即使在接受最大限度治疗、血浆低密度脂蛋白胆固醇水平较低的个体中，冠心病的残余风险仍然存在。 流行病学和遗传学研究表明，相当大比例的残余风险是由于 富含甘油三酯的载脂蛋白(ApoBCL)的血浆水平。包括以下三个项目 该计划项目拨款(PPG)将阐明调节合成的新分子机制， 载脂蛋白BCL的分泌和代谢。我们的PPG由杰出的调查人员组成，具有长期的 合作历史，其中五人(戈尔茨坦、布朗、霍布斯、霍顿和科恩)曾共同工作过 25年。在这个新的PPG的项目1中，Radhakrishnan，Brown和Goldstein使用了原始的和 创新的筛选方法来鉴定与SCAP高结合的类胆固醇小分子 SREBPs是一种转录因子，它可以激活细胞周期调控所需的基因 胆固醇、脂肪酸(FAs)和甘油三酯(TGS)的合成。这种化合物将被用来阐明 SCAP感知甾醇的分子机制，使首次描述SCAP的胆固醇结合成为可能 站点的原子分辨率。目前正在开发的胆固醇模拟化合物和更有效的衍生物 将用于评估SCAP抑制剂降低血浆载脂蛋白BCL的临床意义。在项目中 2、Horton、Kim和Leung在肝脏中发现了一种新的造脂酶复合体。他们将表现出 脂肪酸合成复合体的组成，并确定该复合体如何与额外的FA修饰相互作用 合成TGS和ApoBCL所需的蛋白质和酰基转移酶。完成拟议的研究 将确定新的治疗干预机会，以减少FAs、TGS和VLDL的合成。在……里面 项目3，Hobbs和Cohen使用基于种群的重新测序来识别功能缺失突变 血管生成素样蛋白(ANGPTL)3和8。他们表明，这两种蛋白中的任何一种的突变都会导致血浆低密度脂蛋白- 胆固醇和甘油三酯水平。他们的研究将阐明载脂蛋白BCL降低效应的机制 Angptl3和ANGPTL8。在这个过程中，他们将定义一种新的途径，促进载脂蛋白BCL的清除 不依赖于低密度脂蛋白受体。 研究项目将得到三个核心的支持：行政、组织培养和抗体生产， 和质谱学。 该PPG的成员有着长期的协作互动记录和卓越的工作效率。我们 将继续关注旨在回答关键问题的大胆假设。调查人员带着 以发表具有原创性和科学严谨性为特点的论文而特别自豪。这个 我们的项目的成功完成为揭示新的治疗机会带来了巨大的希望 用于降低血浆载脂蛋白和残余心血管风险。