Advanced Glycation Endproducts and Cardio-Renal Disease

项目摘要/摘要 目前的申请建议将候选人的计划推进到以患者为导向 通过组学科学方面的正式培训进行研究，并通过提高 指导年轻的调查人员，并通过一个研究项目，该项目将建立在 候选人以前的工作，并提供机会发展他的组学研究门户。这个 研究项目旨在弥合关于关键先进技术重要性的知识差距 糖基化终末产物(AGEs)在普通人群中与心血管和肾脏疾病有关。至 为此，它将对由主要等离子体组成的面板进行金标准测量 AGEs，特别是数量上和功能上最重要的加合物--甲基乙二醛 氢咪唑酮(MG-H1)和3-脱氧葡萄糖酮-氢咪唑酮(3DG-H)，它们有 到目前为止，几乎没有在一般临床或人群环境中进行评估。对于目标1，该项目 将利用一项正在进行的研究，应用最先进的超声心动图和磁力 核磁共振成像(MRI)对感染或有HIV感染风险的妇女的研究 机构间艾滋病毒研究(WIHS)评估血浆AGEs与心肌异常的关系 在这个高危人群中的机械性和纤维化。对于目标2和目标3，该项目将充分利用 肾小球滤过系列测量的可用性和标准化确定 中老年人心血管事件的多种族研究 动脉粥样硬化(MESA)研究血浆AGEs与糖尿病进展的关系 慢性肾脏疾病和突发心血管疾病。这些研究将为受训人员提供 与临床和流行病学研究的一系列接触，使他们能够发展为 调查人员。此外，遗传/基因组、表观基因组、转录和代谢组学的有效性 MESA的数据将允许探索年龄水平的组学相关性，为 在未来进行更大规模的调查。因此，结合正规的课程作业， 加强指导，并利用现有研究基础设施解决研究问题 具有重大临床重要性的问题将为候选人提供更多的能力 精准医学，并为他的学员提供成长的机会 这一学科和其他学科的研究人员。

PROJECT SUMMARY/ABSTRACT The current application proposes to advance the candidate's program in patient-oriented research through formal training in omics science and mentorship, through an increased level of mentoring of young investigators, and through a research project that will build on the candidate's previous work and afford opportunities to develop his omics research portolio. The research project aims to close knowledge gaps regarding the significance of key advanced glycation endproducts (AGEs) to cardiovascular and renal disease in the general population. To this end, it will undertake gold-standard measurement of a panel comprising the major plasma AGEs, and particularly the quantitatively and functionally most important adducts, methylglyoxal hydroimidazolone (MG-H1) and 3-deoxyglucosone-hydroimidazolones (3DG-H), which have scarcely been evaluated in general clinical or population settings to date. For Aim 1, the project will leverage an ongoing study applying state-of-the-art echocardiography and magnetic resonance imaging (MRI) in women with, or at risk for HIV infection, in the Women's Interagency HIV Study (WIHS) to evaluate the relation of plasma AGEs to abnormal myocardial mechanics and fibrosis in this high-risk population. For Aims 2 and 3, the project will parlay the availability of serial measures of glomerular filtration and standardized ascertainment of cardiovascular events among middle-aged to older adults from the Multi-Ethnic Study of Atherosclerosis (MESA) to investigate the associations of plasma AGEs with progression of chronic kidney disease and incident cardiovascular disease. These studies will provide trainees with a range of exposures to clinical and epidemiologic research to allow their development as investigators. Further, availability genetic/genomic, epigenomic, transcriptomic and metabolomic data in MESA will permit exploration of the omic correlates of AGE levels, setting the stage for larger-scale investigations in the future. Hence, the combination of formal coursework, increased mentorship, and the leveraging of existing research infrastructure to address research questions of major clinical importance will provide the candidate with increased capabilities for POR in precision medicine, and afford opportunities for the growth of his mentees as researchers in this and other disciplines.