Metabolite Profiling and Cardiovascular Mortality in End-stage Renal Disease

终末期肾病的代谢分析和心血管死亡率

• 批准号: 8303306
• 负责人: EUGENE P. RHEE
• 金额: $ 15.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303306
• 关键词: Adipic Acids; Affect; Bioethics; Blood; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Choline; Chronic Kidney Failure; Clinical; Clinical Research; Cohort Studies; Data; Development Plans; Disease Progression; Emerging Technologies; End stage renal failure; Enrollment; Environment; Etiology; Faculty; Fellowship; Funding; Future; General Hospitals; Glomerular Filtration Rate; Goals; Heart; Heart Diseases; Hemodialysis; Individual; Institutes; Internal Medicine; Investigation; Kidney; Kidney Diseases; Kynurenic Acid; Laboratories; Lead; Link; Liquid Chromatography; Massachusetts; Measures; Mentors; Mentorship; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metric; Modality; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrology; Outcome; Outpatients; Pathogenesis; Pathology; Pathway interactions; Patients; Pennsylvania; Peritoneal; Plasma; Population; Positioning Attribute; Renal function; Research; Research Personnel; Residencies; Resources; Risk Marker; Staging; Testing; Therapeutic; Training; Translational Research; Universities; Uremia; Waste Products; Woman; Work; base; cardiovascular risk factor; career development; case control; cohort; design; experience; heart disease risk; insight; interest; liquid chromatography mass spectrometry; metabolomics; mortality; novel; novel therapeutic intervention; programs; research study; small molecule; tandem mass spectrometry

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.

描述（由申请人提供）：该提案将液相色谱，基于质谱的代谢物分析与表征良好的患者同类结合在一起，以识别和表征新颖的末期肾脏疾病（ESRD）中新型心血管风险标记。该项目直接参与了两个NIDDK研究计划：1）功能代谢组学，该功能代谢组学用于“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学之间的新的，潜在的机械关系”； 2）末期肾脏疾病，“支持对尿毒症状态的发病机理的研究，以及腹膜和血液透析的末期肾脏疾病治疗”。候选人：Eugene Rhee从宾夕法尼亚大学获得了MD和MA Bioethics，并在MGH/ Brigham＆妇女计划中完成了马萨诸塞州综合医院（MGH）（MGH）（MGH）的内科住院医师和首席居住。他目前正在MGH肾脏病学部门担任教职员工。他正在接受一个致力于了解代谢疾病血管并发症的实验室培训，并获得了Broad Institute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资助的研究者。环境：Rhee博士的导师提供互补的专业知识。罗伯特·格斯茨（Robert Gerszten）博士是Broad代谢物分析平台的共同点，也是MGH心脏中心转化研究主管。 Ravi Thadhani博士是MGH肾脏科临床研究主任，在ESRD研究方面具有强大的背景。两位调查人员都有强大的指导记录。申请人的职业发展计划需要在代谢物分析，直接经验和临床研究课程方面进行严格的培训，以及来自科学顾问的多样化和专用网络的密切指导。研究：该提议建立在初步实验的基础上，该实验突出了ESRD中某些代谢途径的改变，特别是前进了3个候选代谢物 - 脂肪酸，雌二酸和胆碱 - 具有与心血管癌症的潜在相关性。在AIM 1中，将对参加纵向ESRD队列研究的患者的血浆（Armorr-肾脏替代的加速死亡率）进行代谢物分析。使用嵌套的病例对照设计，将将来自心血管原因一年内死亡的个体的代谢物概况与至少一年生存的人的代谢物概况进行比较。在AIM 2中，将检查这些患者的血液透析强度与代谢物谱之间的关系。在AIM 3中，将对具有肾脏疾病较早阶段的个体进行代谢产物分析，以确定肾功能与代谢物谱之间的关系。最终，确定ESRD中新型的心血管风险标志物，了解它们如何受到血液透析的影响，并认识到它们在疾病进展过程中何时出现，可以产生新的指标来评估ESRD并导致新的治疗方法。