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

项目摘要/摘要 这项提案详细说明了一项为期五年的全面培训计划，该计划旨在 功能基因组学在心血管预防医学中的应用。申请人寻求使用DNA适体 基于人体血浆和基因组学数据的蛋白质组学图谱数据，以确定新的途径 动脉粥样硬化的发病机制，然后可以用动物，细胞和分子生物学技术来研究。 这位候选人即将完成他在心血管内科的临床研究，并将加入贝思的教职。 以色列女执事医疗中心毕业。概述的方案建立在候选人的临床基础上 在获得药理学博士学位后，他在分子和细胞研究方面的培训和深厚的背景 通过实验室工作、教学课程、研讨会和 科学会议：功能基因组学中的生物信息学和心血管小鼠模型的使用 疾病。这位候选人的导师是基于群体的多组学分子图谱方面公认的领导者 研究并将这些发现转化为基于细胞和动物的模型系统。科学咨询 委员会在人类基因组学、小鼠模型等方面拥有卓越的指导记录和丰富的专业知识 动脉粥样硬化和新陈代谢以及基因编辑。 拟议的研究扩展了将蛋白质组学和基因组学数据整合在一起的初步研究 两项大规模基于人群的研究，以确定磷酸酶PPM1G和PPM1G之间的新关联 血浆载脂蛋白E(ApoE)水平。这种联系在体外通过敲打得到了实验验证。 在人肝细胞模型中下调PPM1G，导致载脂蛋白E显著和特异性下调 转录和载脂蛋白E水平。申请者现在提议测试PPM1G是一种 新的载脂蛋白E生物学调节因子在小鼠体内早期动脉粥样硬化发病机制中的作用 模特们。在目标1中，申请者将测试PPM1G基因敲除是否调节小鼠的ApoE表达。 在目标2中，申请人将研究PPM1G基因敲除是否调节动脉粥样硬化病变的形成。 在小鼠模型中。在目标3中，申请人将扩展他的功能基因组学研究，以确定其他 动脉粥样硬化发病机制中的新途径，并在模型系统中测试它们的功能效应。 尽管预防心脏病学取得了巨大的进步，但动脉粥样硬化性心血管疾病仍然存在 是世界范围内死亡的主要原因。这种残留的疾病负担可能反映了重要的、未被发现的 动脉粥样硬化形成的基础和现有治疗方法尚未有效靶向的生物途径。 这项提议旨在利用新兴的功能基因组学方法在早期发现新的通路 动脉粥样硬化症。通过强调新的途径，这项研究可能最终导致新的目标 预防性动脉粥样硬化治疗。

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.