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The Role of PPM1G in Apolipoprotein E Biology and Atherosclerotic Cardiovascular Disease

PPM1G 在载脂蛋白 E 生物学和动脉粥样硬化性心血管疾病中的作用

基本信息

批准号：
10308397
负责人：
Mark Daniel Benson
金额：
$ 16.74万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-11 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308397
关键词：
Address Adult Advisory Committees Animals Apolipoprotein E Arterial Fatty Streak Atherosclerosis Back Bioinformatics Biological Biological Markers Biological Models Biology CRISPR/Cas technology Cardiology Cardiometabolic Disease Cardiovascular Diseases Cardiovascular system Cells Cellular biology Childhood Cholesterol Chronic Disease Clinical Complex DNA Disease Doctor of Philosophy Down-Regulation E protein Educational workshop Faculty Fellowship Foundations Framingham Heart Study Future Gene Expression Genes Genetic Genetic Transcription Genome Scan Genomic approach Goals Heart Diseases Hepatocyte Human In Vitro Individual Inflammation Israel Laboratories Lead Lipids Liver Maps Measures Medical center Medicine Mentors Metabolism Modeling Molecular Molecular Biology Techniques Molecular Profiling Mus Participant Pathogenesis Pathway interactions Peripheral arterial disease Pharmacology Pilot Projects Plasma Population Study Preventive Process Protein phosphatase Proteins Proteome Proteomics Regulatory Pathway Research Residual Tumors Risk Risk Factors Role Serotyping Small Interfering RNA Source Stress Stroke System Techniques Technology Testing Training Training Programs Translating Vascular Diseases Viral Work aptamer atherogenesis base burden of illness cardiovascular disorder risk career development clinical candidate cohort experience functional genomics genetic variant genome wide association study genomic data human data human genomics in vivo interest knock-down mortality mouse model multiple omics new therapeutic target novel offspring protein profiling rare variant response risk variant symposium western diet

项目摘要

PROJECT SUMMARY/ABSTRACT This proposal details a comprehensive five-year training program for mentored career development in functional genomics applied to preventive cardiovascular medicine. The applicant seeks to use DNA-aptamer based proteomics profiling data from human plasma and genomics data to identify novel pathways in atherosclerotic pathogenesis that can then be studied using animal, cell and molecular biology techniques. The candidate is completing his clinical fellowship in cardiovascular medicine and will join the faculty at Beth Israel Deaconess Medical Center upon graduation. The outlined proposal builds on the candidate’s clinical training and strong background in molecular and cellular research following his Ph.D. in pharmacology to provide two new domains of expertise through a blend of laboratory work, didactic courses, workshops, and scientific conferences: bioinformatics in functional genomics and the use of murine models of cardiovascular disease. The candidate’s mentor is a recognized leader in multi-omics molecular profiling in population-based studies and translating these findings back to cell- and animal-based model systems. The scientific advisory committee has a distinguished mentoring record and vast expertise in human genomics, murine models of atherosclerosis and metabolism, and gene editing. The proposed research extends preliminary studies that integrated proteomics and genomics data in two large population-based studies to identify a novel association between the phosphatase PPM1G and plasma levels of apolipoprotein E (ApoE). This association was experimentally validated in vitro by knocking down PPM1G in a human hepatocyte model, which led to the significant and specific down-regulation of ApoE transcription and ApoE protein levels. The applicant now proposes to test the hypothesis that PPM1G is a novel regulator of ApoE biology and contributes to early atherosclerotic pathogenesis in vivo using mouse models. In Aim 1, the applicant will test whether knockdown of PPM1G modulates ApoE expression in mice. In Aim 2, the applicant will examine whether knockdown of PPM1G modulates atherosclerotic lesion formation in murine models. In Aim 3, the applicant will expand his functional genomics studies to identify additional novel pathways in atherosclerotic pathogenesis and test their functional effects in model systems. Despite tremendous progress in preventive cardiology, atherosclerotic cardiovascular disease remains the leading cause of mortality worldwide. This residual disease burden likely reflects important, undiscovered biological pathways that underlie atherogenesis and that are not yet effectively targeted by available therapies. This proposal aims to use emerging functional genomics approaches to identify novel pathways in early atherosclerotic disease. By highlighting novel pathways, this research may ultimately lead to new targets for preventive atherosclerotic therapy.

项目总结/文摘