The effects of protein carbamylation in end stage kidney disease

蛋白质氨甲酰化对终末期肾病的影响

• 批准号: 9267448
• 负责人: Sahir Kalim
• 金额: $ 16.32万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-30 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267448
• 关键词: Affect; Amino Acids; Animals; Appointment; Atherosclerosis; Basic Science; Binding; Biochemical; Blood Urea Nitrogen; Blood specimen; Cardiac; Cardiovascular system; Cessation of life; Charge; Clinical; Clinical Research; Cohort Studies; Collagen; Data; Dialysis patients; Dialysis procedure; End stage renal failure; Environment; Epidemiology; Event; Excess Mortality; Faculty; Fellowship; Fellowship Program; Functional disorder; Funding; General Hospitals; General Population; Goals; Health; Hemodialysis; Hospitals; Human; In Vitro; Individual; Inflammatory; Internal Medicine; Intervention; Intervention Studies; Investments; Kidney Failure; Kinetics; Knowledge; Length; Link; Low-Density Lipoproteins; Maintenance; Massachusetts; Master' s Degree; Measures; Mediating; Mediator of activation protein; Medical; Medicare; Mentors; Mentorship; Methods; Modality; Molecular; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Nephrology; New York City; Nutritional; Outcome; Pathologic; Patient-Focused Outcomes; Patients; Peritoneal; Pilot Projects; Post-Translational Protein Processing; Process; Proteins; Public Health; Publishing; Quality of life; Randomized Clinical Trials; Reaction; Recombinant Erythropoietin; Renal function; Research; Research Personnel; Research Training; Resources; Risk; Science; Stress; Structure; Supplementation; Testing; Time; Toxic effect; Training; United States National Institutes of Health; Universities; Urea; Vermont; Woman; amino group; carbamylated erythropoietin; cardiovascular risk factor; cohort; conventional therapy; cost; faculty research; improved; indexing; inflammatory marker; medical schools; mortality; new therapeutic target; nitrogen metabolism; novel; novel therapeutic intervention; novel therapeutics; prevent; programs; prospective; protein function; public health relevance

 DESCRIPTION (provided by applicant): Aligning with the NIH-NIDDK End-Stage Renal Disease (ESRD) Program's goal of "promoting research to reduce the morbidity and mortality from ESRD," this proposal focuses on understanding the fundamental causes of the excess morbidity and mortality seen in dialysis patients in an effort to develop new targeted therapies. Candidate: Sahir Kalim completed his medical degree at the University of Vermont, his internal medicine training at the Mount Sinai Hospital in New York City, and his nephrology fellowship training at the combined Massachusetts General Hospital (MGH)/ Brigham and Women's Hospital Nephrology Fellowship Program. He recently completed a Master's Degree in Medical Science at Harvard Medical School (HMS). Dr. Kalim holds a faculty appointment in the MGH Nephrology Division and at HMS. His long term goal is to become an R01 funded investigator with expertise in ESRD, uremic toxicity, and human trials. Environment and Mentors: MGH and HMS offer a highly reputed clinical research training environment with a large pool of exceptional research faculty and several resources of particular value to junior investigators. Dr. Kalim's mentors provide complementary expertise: Dr. Ravi Thadhani is Director of Clinical Research as well as Chief of the MGH Nephrology Division and Dr. Ananth Karumanchi is a Howard Hughes Investigator whose lab has made several basic science contributions directly relevant to this proposal. Both Drs. Thadhani and Karumanchi have a robust track record of mentorship and a strong commitment to Dr. Kalim's training. Research: Growing evidence suggests a harmful protein modification known as carbamylation occurs in the setting of elevated urea levels from kidney failure, yet significant gaps persist in our knowledge of this process. This proposal examines the epidemiology of protein carbamylation in ESRD and how novel interventions might reduce carbamylation and improve health. Aim 1 utilizes existing data and blood samples, obtained as part of a large prospective observational cohort study of dialysis patients, to identify which variables influence carbamylation, which clinical outcomes carbamylation associates with, and how different dialysis modalities effect carbamylation levels. Studying over 500 individuals to understand the epidemiology of protein carbamylation-its mediators and its consequences-will improve our knowledge of the unique pathophysiology of ESRD and inform approaches to treatment. Notably, carbamylation occurs on both proteins and free amino acids and these targets effectively compete with each other for binding. Preliminary data suggest giving amino acid supplementation to dialysis patients significantly reduces carbamylation. Thus, Aim 2 of this proposal is a randomized clinical trial in 60 maintenance hemodialysis patients testing the effects of amino acid supplementation on carbamylation and clinical outcomes. Together, understanding the effects of protein carbamylation in ESRD and how best to treat it could yield new metrics by which to assess dialysis efficacy as well as new therapeutic approaches to improve patient outcomes in ESRD.

 描述（由申请人提供）：与NIH-NIDDK终末期肾病（ESRD）计划的目标“促进研究以降低ESRD的发病率和死亡率”一致，本提案侧重于了解透析患者中观察到的过度发病率和死亡率的根本原因，以开发新的靶向治疗。候选人：Sahir Kalim在佛蒙特大学完成了医学学位，在纽约市西奈山医院完成了内科培训，并在联合马萨诸塞州总医院（MGH）/布里格姆和妇女医院肾脏病奖学金计划完成了肾脏病奖学金培训。他最近在哈佛医学院（HMS）完成了医学科学硕士学位。Kalim博士在MGH肾脏科和HMS担任教职。他的长期目标是成为一名R 01资助的研究人员，在ESRD，尿毒症毒性和人体试验方面具有专业知识。环境与导师：MGH和HMS提供了一个高度知名的临床研究培训环境，拥有大量优秀的研究人员和对初级研究人员特别有价值的几个资源。博士 Kalim的导师提供了互补的专业知识：Ravi Thadhani博士是临床研究主任，也是MGH肾脏科主任，Ananth Karumanchi博士是霍华德休斯研究员，他的实验室做出了与此提案直接相关的几项基础科学贡献。Thadhani博士和Karumanchi博士都有良好的指导记录，并对Kalim博士的培训做出了坚定的承诺。调研：越来越多的证据表明，一种被称为氨甲酰化的有害蛋白质修饰发生在肾衰竭导致的尿素水平升高的情况下，但我们对这一过程的认识仍存在重大差距。该提案研究了ESRD中蛋白质氨甲酰化的流行病学，以及新的干预措施如何减少氨甲酰化并改善健康。目的1利用现有数据和血液样本，作为透析患者的大型前瞻性观察性队列研究的一部分，以确定哪些变量影响氨甲酰化，氨甲酰化与哪些临床结局相关，以及不同的透析方式如何影响氨甲酰化水平。研究超过500人，以了解蛋白质氨甲酰化的流行病学-其介质及其后果-将提高我们对ESRD独特病理生理学的认识，并为治疗方法提供信息。值得注意的是，氨甲酰化发生在蛋白质和游离氨基酸上，这些靶标有效地相互竞争结合。初步数据表明，给透析患者补充氨基酸可显著降低氨甲酰化。因此，本提案的目的2是在60名维持性血液透析患者中进行的随机临床试验，以检测氨基酸补充对氨甲酰化和临床结局的影响。总之，了解蛋白质氨甲酰化在ESRD中的作用以及如何最好地治疗它可以产生新的指标来评估透析疗效以及改善ESRD患者结局的新治疗方法。