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: 9118257
• 负责人: Sahir Kalim
• 金额: $ 15.74万
• 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/9118257
• 关键词: Accounting; 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; Myocarditis; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Nephrology; New York City; Nutritional; Outcome; 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; 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 structure 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（由适用提供）：与NIH-NIDDK终末期肾脏疾病（ESRD）计划“促进研究以降低ESRD的发病率和死亡率”的目标，该提案着重于理解透析患者中​​过度发病率和死亡率的根本原因，以开发新的目标治疗。候选人：萨希尔·卡里姆（Sahir Kalim）在佛蒙特大学（University of Vermont），纽约市西奈山医院的内科培训以及他在马萨诸塞州联合医院（MGH）/布里格姆医院肾脏医院肾脏学奖学金计划的肾脏学研究金培训中获得了医学培训。他最近在哈佛医学院（HMS）完成了医学硕士学位。 Kalim博士担任MGH肾脏科和HMS的教师任命。他的长期目标是成为R01资助的研究人员，具有ESRD，尿毒症毒性和人类试验的专业知识。环境和导师：MGH和HMS提供了高度再现的临床研究培训环境，其中有大量的杰出研究教师和对初级研究人员的一些特殊价值的资源。博士 Kalim的导师提供了完整的专业知识：Ravi Thadhani博士是临床研究主任以及MGH肾脏病科负责人，而Ananth Karumanchi博士是霍华德·休斯（Howard Hughes）的一名研究员，其实验室的实验室与该提案直接相关。两个博士。 Thadhani和Karumanchi对Kalim博士的培训有着强大的心态记录和坚定的承诺。研究：越来越多的证据表明，一种有害的蛋白质修饰称为卡氨基化，发生在肾衰竭因尿素水平升高的情况下，但我们对这一过程的了解仍然存在。该建议检查ESRD中蛋白质氨基甲基化的流行病学以及新颖的干预措施如何减少甲酰胺化并改善健康状况。 AIM 1利用现有的数据和血液样本，作为对透析患者的大型前瞻性观察队列研究的一部分，以确定哪些变量会影响卡氨基化，而卡氨基化的carbamylation与carbamylation的临床结局与与不同的透析透析模态效应碳酰基化水平。研究超过500个人，以了解蛋白质氨基甲基化介质的流行病学及其后果，而不会改善我们对ESRD独特的病理生理学的知识和信息治疗方法。值得注意的是，卡氨基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以结合结合。初步数据表明，为透析患者补充氨基酸可显着降低卡氨基化。这是该提案的目标2是一项随机临床试验，对60名维持血液透析患者测试了补充氨基酸对氨基酸和临床结果的影响。共同了解蛋白质氨基甲基化在ESRD中的影响以及如何最好地治疗它可以产生新的指标，以评估透析效率以及新的治疗方法，以改善ESRD的患者结果。