Metabolite Profiling and Cardiovascular Mortality in End-stage Renal Disease

描述(由申请人提供)：这项建议将基于高效液相色谱、质谱学的代谢物分析与特征良好的患者队列相结合，以识别和表征终末期肾脏疾病(ESRD)的新心血管风险标记物。该项目直接参与了NIDDK的两个研究项目：1)功能代谢组学，它应用代谢组学来“发现代谢物变化与特定代谢性疾病或综合征的病因或病理之间的新的、潜在的机制关系”；以及2)终末期肾脏疾病，它“支持尿毒症状态的发病机制的研究，[和]通过腹膜和血液透析治疗终末期肾脏疾病”。候选人：Eugene Rhee在宾夕法尼亚大学获得医学博士和生物伦理学硕士学位，并在马萨诸塞州综合医院(MGH)完成内科住院医师和首席住院医师，并在MGH/Brigham&Women‘s合并项目中获得肾病学奖学金；他目前是MGH肾病科的教员。他正在一家致力于了解代谢性疾病血管并发症的实验室接受培训，并在布罗德研究所获得独特的代谢物分析资源。申请者的长期目标是成为一名拥有尿毒症专业知识的R01资助的研究人员。环境：李博士的导师提供互补的专业知识。Robert Gerszten博士是布罗德代谢物分析平台的联合PI，也是麻省理工学院心脏中心的翻译研究主任。Ravi Thadhani博士是麻省理工学院肾脏科临床研究部主任，在ESRD研究方面有很强的背景。这两位调查人员在指导方面都有良好的记录。申请者的职业发展计划需要在代谢物分析方面进行严格的培训，在临床研究方面有直接的经验和课程，以及来自多样化和专注的科学顾问网络的密切指导。研究：这项建议建立在初步实验的基础上，这些实验强调了ESRD选定的代谢途径的变化，并特别提出了3种候选代谢物-己二酸、犬尿酸和胆碱-与心血管结果潜在相关。在目标1中，将对参加纵向ESRD队列研究(ARMORR-肾脏置换加速死亡率)的患者的血浆进行代谢物分析。使用嵌套病例对照设计，将心血管原因一年内死亡的个体的代谢物图谱与存活至少一年的个体的代谢物图谱进行比较。在目标2中，将检查这些患者的血液透析强度和代谢物分布之间的关系。在目标3中，将对患有早期肾病的个体进行代谢物图谱分析，以确定肾功能和代谢物图谱之间的关系。最终，识别ESRD中新的心血管风险标记物，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，可能会产生新的指标来评估ESRD，并导致新的治疗方法。 公共卫生相关性：患有肾脏疾病，特别是终末期肾脏疾病的人患心脏病的风险显著增加。这项提议的目标是确定新的血液标志物，预测终末期肾病患者的心血管死亡，并为为什么肾脏疾病增加心脏病风险提供新的见解。

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.