New Approaches to Reduce Residual Cardiovascular Risk

降低残余心血管风险的新方法

• 批准号: 10332592
• 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/10332592
• 关键词: ANGPTL3 gene; Acetyl-CoA Carboxylase; Angiopoietins; Animals; Antibody Formation; Apolipoproteins B; Binding; Binding Proteins; Binding Sites; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cholesterol; Clinical; Collaborations; Complex; Coronary heart disease; Cytosol; DNA Resequencing; 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; Low-Density Lipoproteins; 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; Transferase; Triglycerides; Variant; Very low density lipoprotein; Work; activating transcription factor; 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：减少残留心血管风险的新方法 摘要/摘要 在过去的40年中，通过降低血浆来减少心血管事件取得了重大进展 LDL-胆固醇（LDL-C）。他汀类药物和PCSK9抑制剂有效地降低了LDL-C水平，但显着 即使在血浆较低的LDL-C水平的最大治疗个体中，CHD的残留风险仍然存在。 流行病学和遗传研究表明，剩余风险很大一部分是由于升高 富含甘油三酸酯的血浆水平富含APOB的脂蛋白（APOBCL）。完成的三个项目 该计划项目赠款（PPG）将阐明调节合成的新分子机制， 分泌和apobcls的代谢。我们的PPG由杰出研究者组成，长期存在 合作的历史，其中五个（戈德斯坦，布朗，霍布斯，霍顿和科恩）共同努力 25年。在这个新PPG的项目1中，Radhakrishnan，Brown和Goldstein使用了原创和 创新的筛选方案，以识别胆固醇模拟的小分子，该分子结合高于SCAP 特异性和阻断SREBP的激活，这是激活基因所需的转录因子 胆固醇，脂肪酸（FAS）和甘油三酸酯（TGS）的合成。该化合物将用于阐明 SCAP感觉立体声的分子机制，使SCAP胆固醇结合的首次描述 位于原子分辨率。当前的胆固醇模拟化合物和发育中更多的潜在衍生物 将用于评估SCAP抑制剂减少血浆APOBCL的临床意义。在项目中 2，Horton，Kim和Liang已经确定了肝脏中新的脂肪生物酶复合物。他们会表征 FA合成复合物的组件，并确定该复合物如何与其他FA修饰相互作用 合成TG和APOBCL所需的蛋白质和酰基转移酶。拟议研究的完成 将确定治疗干预措施的新机会，以减少FAS，TGS和VLDL的合成。在 项目3，Hobbs和Cohen使用基于人群的重新配置来识别功能丧失突变 血管生成素样（Angptl）3和8。 胆固醇和TG水平。他们的研究将阐明APOBCL降低效应的机制 Angptl3和Angptl8的在此过程中，他们将定义一种促进APOBCL清除率的新途径 独立于LDL接收器。 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。 该PPG的成员在协作互动和出色的生产力方面有很长的记录。我们 将继续专注于旨在回答关键问题的大胆假设。调查人员接受 以出版论文为特征的特征是独创性和科学严峻的特征。这 成功完成我们的项目有很大的希望可以暴露新的治疗机会 用于减少血浆APOBCL和残留的心血管风险。