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：降低剩余心血管风险的新方法 总结/摘要 在过去的40年里，通过降低血浆中的 LDL-胆固醇（LDL-C）。虽然他汀类药物和PCSK 9抑制剂有效降低LDL-C水平，但显著 即使在接受最大剂量治疗且血浆LDL-C水平较低的个体中，CHD的剩余风险仍然存在。 流行病学和遗传学研究表明，很大一部分剩余风险是由于 血浆中富含谷胱甘肽的含ApoB脂蛋白（ApoBCL）水平。这三个项目包括 这项计划项目补助金（PPG）将阐明新的分子机制，调节合成， ApoBCL的分泌和代谢。我们的PPG由杰出的研究人员组成， 合作的历史，其中五人（戈尔茨坦，布朗，霍布斯，霍顿和科恩）曾在一起工作， 25年在这个新PPG的项目1中，Radhakrishnan，Brown和Goldstein使用了一个原始的， 创新的筛选方案，以鉴定与Scap结合的胆固醇模拟小分子， 特异性和阻断SREBPs的激活，SREBPs是激活免疫调节所需基因的转录因子。 胆固醇、脂肪酸（FA）和甘油三酯（TG）的合成。该化合物将用于阐明 Scap感知固醇的分子机制，使Scap的胆固醇结合的第一个描述 原子分辨率的网站。目前的胆固醇模拟化合物和开发中的更有效的衍生物 将用于评估Scap抑制剂降低血浆ApoBCL的临床意义。在项目 2、Horton、Kim和Liang在肝脏中发现了一种新的脂肪生成酶复合物。他们会描述 FA合成复合物的组分，并确定该复合物如何与额外的FA修饰 合成TG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，以减少脂肪酸，甘油三酯和极低密度脂蛋白的合成。在 项目3中，Hobbs和Cohen使用基于群体的重测序来识别基因组中的功能缺失突变。 血管生成素样（ANGPTL）3和8。他们发现，任何一种蛋白质的突变都会导致血浆LDL水平降低， 胆固醇和TG水平。他们的研究将阐明ApoBCL降低作用的机制 ANGPTL 3和ANGPTL 8。在此过程中，他们将确定一种新的途径，促进ApoBCL的清除 独立于LDL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， 和质谱分析。 该PPG的成员拥有长期的协作互动和卓越的生产力记录。我们 将继续专注于大胆的假设，旨在回答关键问题。调查人员采取 对发表具有原创性和科学严谨性的论文感到特别自豪。的 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 降低血浆ApoBCL和心血管残余风险。