Metabolite Profiling and Cardiovascular Mortality in End-stage Renal Disease

描述（由申请人提供）：本提案将基于液相色谱、质谱的代谢物分析与特征明确的患者队列相结合，以识别和表征终末期肾病（ESRD）中新的心血管危险标志物。该项目直接涉及NIDDK的两个研究项目：1)功能代谢组学，将代谢组学应用于“发现代谢物谱变化与特定代谢性疾病或综合征的病因或病理之间新的、潜在的机制关系”；2)终末期肾病，“支持研究尿毒症的发病机制，[和]通过腹膜透析和血液透析治疗终末期肾病”。候选人：Eugene Rhee获得宾夕法尼亚大学生物伦理学博士和硕士学位，在马萨诸塞州总医院（MGH）完成内科住院医师和首席住院医师，并在MGH/ Brigham & Women's联合项目中获得肾脏病学奖学金；他目前是MGH肾脏病科的教员。他正在一个实验室接受培训，致力于了解代谢性疾病的血管并发症，并获得Broad研究所独特的代谢物分析资源。申请人的长期目标是成为具有尿毒症专业知识的R01资助研究者。环境：李博士的导师提供互补的专业知识。Robert Gerszten博士是Broad代谢物分析平台的共同负责人，也是MGH心脏中心的转化研究主任。Ravi Thadhani博士是MGH肾脏病科临床研究主任，在ESRD研究方面有很强的背景。两位调查员都有良好的指导记录。申请人的职业发展计划包括在代谢物分析方面的严格培训，临床研究的直接经验和课程，以及来自多样化和专业的科学顾问网络的密切指导。研究：该提案建立在初步实验的基础上，强调了ESRD中选择代谢途径的改变，并特别提出了3种候选代谢物-己二酸，尿尿酸和胆碱-与心血管结局的潜在相关性。在Aim 1中，将对纵向ESRD队列研究（ArMORR -肾脏替代加速死亡率）患者的血浆进行代谢物分析。采用嵌套病例对照设计，将一年内因心血管原因死亡的个体的代谢物谱与存活至少一年的个体的代谢物谱进行比较。在Aim 2中，将检查这些患者血液透析强度和代谢物谱之间的关系。在Aim 3中，将对早期肾病患者进行代谢物谱分析，以确定肾功能与代谢物谱之间的关系。最终，识别ESRD中新的心血管危险标志物，了解它们如何受到血液透析的影响，并识别它们在疾病进展过程中何时出现，可以产生评估ESRD的新指标，并产生新的治疗方法。

DESCRIPTION (provided by applicant): This proposal integrates liquid chromatography, mass spectrometry based metabolite profiling with well- characterized patient cohorts to identify and characterize novel cardiovascular risk markers in end-stage renal disease (ESRD). This project directly engages two NIDDK research programs: 1) Functional Metabolomics, which applies metabolomics towards "discovering new, potentially mechanistic relationships between changes in metabolite profile and the etiology or pathology of specific metabolic diseases or syndromes"; and 2) End- Stage Renal Disease, which "supports investigation on the pathogenesis of the uremic state, [and] on end- stage renal disease treatment by peritoneal and hemodialysis". Candidate: Eugene Rhee received his MD and MA Bioethics from the University of Pennsylvania, and completed Internal Medicine residency and chief residency at the Massachusetts General Hospital (MGH) and Nephrology fellowship in the combined MGH/ Brigham & Women's program; he is currently on faculty in the MGH Nephrology Division. He is pursuing training in a laboratory dedicated to understanding the vascular complications of metabolic disease, with access to a unique metabolite profiling resource at the Broad Institute. The applicant's long-term goal is to become an R01 funded investigator with expertise in uremia. Environment: Dr. Rhee's mentors provide complementary expertise. Dr. Robert Gerszten is a co-PI of the Metabolite Profiling Platform at the Broad, and Director of Translational Research at the MGH Heart Center. Dr. Ravi Thadhani is Director of Clinical Research in the MGH Nephrology Division, with a strong background in ESRD research. Both investigators have a robust track record of mentorship. The applicant's career development plan entails rigorous training in metabolite profiling, direct experience and coursework in clinical research, and close guidance from a diverse and dedicated network of scientific advisors. Research: This proposal builds on preliminary experiments that highlight alterations in select metabolic pathways in ESRD, and specifically advances 3 candidate metabolites - adipic acid, kynurenic acid, and choline - with potential relevance to cardiovascular outcomes. In Aim 1, metabolite profiling will be performed on plasma from patients enrolled in a longitudinal ESRD cohort study (ArMORR - Accelerated Mortality on Renal Replacement). Using a nested case-control design, metabolite profiles from individuals who die within one year of cardiovascular causes will be compared with metabolite profiles from individuals who survive at least one year. In Aim 2, the relationship between hemodialysis intensity and metabolite profiles in these patients will be examined. In Aim 3, metabolite profiling will be performed on individuals with earlier stages of kidney disease to determine the relationship between kidney function and metabolite profiles. Ultimately, identifying novel cardiovascular risk markers in ESRD, understanding how they are affected by hemodialysis, and recognizing when they arise during disease progression could yield new metrics by which to assess ESRD and lead to new therapeutic approaches. PUBLIC HEALTH RELEVANCE: The risk of heart disease is significantly increased in individuals with kidney disease, particularly end-stage renal disease. The goal of this proposal is to identify new blood markers that predict cardiovascular death in patients with end-stage renal disease, and to provide new insights into why kidney disease increases the risk of heart disease.