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

项目概要/摘要 该提案详细介绍了一个全面的五年培训计划， 功能基因组学应用于预防心血管疾病。申请人寻求使用DNA-适体 基于来自人血浆的蛋白质组学分析数据和基因组学数据， 动脉粥样硬化的发病机制，然后可以使用动物，细胞和分子生物学技术进行研究。 该候选人正在完成他的心血管医学临床奖学金，并将加入贝丝学院 以色列女执事医疗中心毕业。概述的提案建立在候选人的临床 在获得博士学位后，他在分子和细胞研究方面受过良好的训练，在药理学上， 通过实验室工作，教学课程，研讨会的混合提供两个新的专业领域， 科学会议：功能基因组学中的生物信息学和心血管疾病小鼠模型的使用 疾病候选人的导师是基于人群的多组学分子谱分析的公认领导者 研究和翻译这些发现回到细胞和动物为基础的模型系统。科学咨询 委员会在人类基因组学、小鼠模型和遗传学方面有着杰出的指导记录和丰富的专业知识。 动脉粥样硬化和代谢，以及基因编辑。 拟议的研究扩展了整合蛋白质组学和基因组学数据的初步研究， 两项基于人群的大型研究，以确定磷酸酶PPM 1G与 血浆载脂蛋白E（ApoE）水平。这种关联在体外实验中得到了验证， 在人肝细胞模型中下调PPM 1G，这导致ApoE的显著和特异性下调 转录和ApoE蛋白水平。申请人现在提出测试PPM 1G是一种 ApoE生物学的新调节剂，并有助于使用小鼠体内的早期动脉粥样硬化发病机制 模型在目标1中，申请方将测试PPM 1G的敲低是否调节小鼠中的ApoE表达。 在目标2中，申请人将检查PPM 1G的敲低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，申请人将扩大其功能基因组学研究，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其功能作用。 尽管在预防心脏病学方面取得了巨大进展，但动脉粥样硬化性心血管疾病仍然存在 是全球死亡的主要原因。这种残留疾病负担可能反映了重要的，未发现的 动脉粥样硬化形成的基础生物学途径，并且尚未被可用的疗法有效地靶向。 该提案旨在使用新兴的功能基因组学方法来识别早期免疫缺陷病毒的新途径。 动脉粥样硬化性疾病通过强调新的途径，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.