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New Approaches to Reduce Residual Cardiovascular Risk

降低残余心血管风险的新方法

基本信息

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
项目类别：
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

项目摘要

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