Protein Carbamylation and the Progression and Complications of CKD

蛋白质氨甲酰化与 CKD 的进展和并发症

• 批准号: 10164779
• 负责人: Sahir Kalim
• 金额: $ 29.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-14 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164779
• 关键词: Address; Adult; Albumins; Amino Acids; Atherosclerosis; Automobile Driving; Biochemical; Biochemical Process; Biological Assay; Biology; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Charge; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Cohort Analysis; Cohort Studies; Data; Diabetes Mellitus; Dialysis procedure; Dietary Intervention; Disease Outcome; Disease Progression; Dissociation; End stage renal failure; Epidemiology; Event; Exposure to; Functional disorder; Future; Glomerular Mesangial Cell; Goals; Heart failure; Hemodialysis; Individual; Investments; Ischemic Stroke; Kidney; Kidney Diseases; Kidney Failure; Life; Link; Longitudinal Studies; Measures; Mission; Modeling; Molecular; Morbidity - disease rate; Myocardial Infarction; National Institute of Diabetes and Digestive and Kidney Diseases; Nutritional; Observational Study; Outcome; Participant; Pathogenesis; Pathologic; Pathway interactions; Patients; Peripheral arterial disease; Phenotype; Plasma; Population; Post-Translational Protein Processing; Proteins; Public Health; Renal function; Research; Research Personnel; Research Project Grants; Resources; Risk; Risk Factors; Sampling; Serum Markers; Structure; Supplementation; Urea; Vulnerable Populations; Work; adjudicate; adverse outcome; biobank; cardiovascular risk factor; cohort; design; effective therapy; follow-up; indexing; inflammatory marker; insight; kidney fibrosis; modifiable risk; mortality; mortality risk; novel; novel therapeutic intervention; protein function; stem; targeted treatment; therapeutic target; treatment strategy

Project Summary/ Abstract 30 million US adults have chronic kidney disease (CKD) arising from diverse causes but commonly resulting in life-threatening complications such as cardiovascular disease (CVD) and progression to end stage renal disease (ESRD). Although we understand much about the epidemiology of CKD and its associations with CVD, the underlying mechanisms of CKD pathogenesis, progression, and complications remain less well understood. In this proposal we seek to comprehensively study a novel risk factor for the progression and complications of CKD known as protein carbamylation. Carbamylation describes a posttranslational protein modification caused, in part, by exposure to urea's dissociation product cyanate. Carbamylation increases with renal insufficiency and can change the charge, structure, and function of proteins, resulting in molecular and cellular dysfunction. Select carbamylated proteins have been shown to accelerate pathological biochemical processes such as atherosclerosis and renal fibrosis. We and others have characterized the associated morbidity and mortality risks of carbamylation in multiple ESRD cohorts, but the impact of carbamylation in the non-dialysis CKD population is unknown. The Chronic Renal Insufficiency Cohort (CRIC), an NIDDK- sponsored longitudinal study of 3,939 individuals with CKD that has stored biospecimens and adjudicated kidney and CV outcomes over an average of 6 years of follow-up, creates the ideal opportunity to meet our study's overall objective: we will rigorously quantify the impact of protein carbamylation (employing validated plasma markers of total body carbamylation burden such as carbamylated albumin, C-Alb) on key clinical outcomes in CKD using the CRIC biorepository. Our central hypothesis is that protein carbamylation independently associates with adverse renal and CV outcomes in people with CKD not yet on dialysis. In Aim 1 of the study we will quantify the association between carbamylation load and clinical outcomes in CKD including CKD progression (defined as 50% reduction in eGFR or progression to ESRD); all-cause mortality; and CV events (heart failure, myocardial infarction, ischemic stroke, or peripheral artery disease events). In Aim 2 we will classify which variables most significantly associate with carbamylation load, potentially identifying future therapeutic targets. Our approach includes assaying C-Alb in baseline samples from CRIC, analyzing outcomes in relation to these levels, and comparing various baseline covariates as predictors of C- Alb levels. The expected result of these studies is a comprehensive understanding of the pathophysiology of protein carbamylation in CKD and its relationship to important clinical outcomes. Such information could establish a modifiable risk factor in this vulnerable population. This proposal will boost the NIDDK's yield on its investment in CRIC while furthering its mission to understand the biology underlying CKD progression and its complications to ultimately advance effective treatment strategies.

项目摘要/摘要 3000万美国成年人患有慢性肾脏疾病（CKD），是由于各种原因引起的，但通常导致 威胁生命的并发症，例如心血管疾病（CVD）和末期肾脏的发展 疾病（ESRD）。尽管我们对CKD的流行病学及其与CVD的关联有很多了解，但 CKD发病机理，进展和并发症的基本机制保持不佳 理解。在此提案中，我们试图全面研究进展的新风险因素 CKD的并发症称为蛋白质氨基甲基化。卡氨基化描述了翻译后蛋白 修改部分是由于暴露于尿素解离产物氰酸盐引起的。卡氨基化随着 肾功能不全，可以改变蛋白质的电荷，结构和功能，从而导致分子和 细胞功能障碍。已显示精选的甲酰化蛋白可以加速病理生化 诸如动​​脉粥样硬化和肾纤维化等过程。我们和其他人已经描述了相关的 多个ESRD队列中甲酰胺化的发病率和死亡率风险，但甲米基在 非透析CKD人群尚不清楚。慢性肾功能不全队列（CRIC），NIDDK- 对3,939名CKD患者的赞助纵向研究，该研究存储了生物测量并进行了裁决 肾脏和简历结果平均6年的随访，为满足我们的理想机会创造了理想的机会 研究的总体目标：我们将严格量化蛋白质氨基甲基化的影响（采用经过验证的蛋白质 在关键临床上 使用CRIC BioreSository在CKD中的结果。我们的中心假设是蛋白质氨基甲基化 在尚未透析的人群中，独立与不良肾脏和CV结局相关联。在目标1中 在研究中，我们将量化CKD中的甲酰胺化负荷与临床结果之间的关联 包括CKD进展（定义为EGFR降低50％或向ESRD进展）；全因死亡率； 和简历事件（心力衰竭，心肌梗塞，缺血性中风或周围动脉疾病事件）。在 AIM 2我们将分类哪些变量最显着与卡氨基化负载相关，可能是 确定未来的治疗靶标。我们的方法包括在Cric的基线样品中分析C-alb， 分析与这些水平有关的结果，并将各种基线协变量作为C-的预测指标 ALB水平。这些研究的预期结果是对 CKD中的蛋白质氨基氨基化及其与重要临床结果的关系。这样的信息可以 在这个脆弱的人群中建立可修改的危险因素。该建议将提高NIDDK的收益率 对CRIC进行投资，同时促进其了解CKD进展的生物学的使命及 最终提高有效治疗策略的并发症。