Understanding the role of the Complement Proteome in progressive Diabetic Kidney Disease

了解补体蛋白质组在进展性糖尿病肾病中的作用

• 批准号: 10596080
• 负责人: Monika Anna Niewczas
• 金额: $ 40.75万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-30 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596080
• 关键词: Acceleration; Address; Biological Markers; CCL2 gene; Characteristics; Chronic; Clinical; Clinical Trials; Cohort Studies; Complement; Complex; Data; Data Reporting; Deceleration; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease Progression; End stage renal failure; Ethnic Origin; Etiology; Evaluation; Goals; Health; Histology; Immunoglobulin G; Inflammation; Inflammatory; Injury to Kidney; Intervention; Kidney; Kidney Failure; Knowledge; Machine Learning; Measurement; Mediating; Mediation; Medicine; Nature; Nested Case-Control Study; Participant; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Phenotype; Pilot Projects; Population; Process; Progressive Disease; Proteins; Proteome; Proteomics; Public Health; Publishing; Renal function; Resolution; Risk; Role; Severity of illness; Signaling Protein; Source; Technology; Tissue Banks; Tissues; Tubular formation; Tumor Necrosis Factor Receptor; United States; aptamer; biobank; cohort; complement pathway; complement system; diabetic; disorder risk; drug development; follow-up; improved; indexing; innovation; insight; member; nephrogenesis; non-diabetic; novel; novel therapeutics; prevent; primary outcome; prospective; random forest; stem; study population; systemic inflammatory response; tool; transcriptomics; urinary

PROJECT SUMMARY / ABSTRACT There is a critical need to identify novel mechanisms of diabetic kidney disease (DKD) that will provide targets for new interventions. Chronic inflammation is one plausible mechanism. Using untargeted high-throughput aptamer proteomics, our recently published study has shed new light on specific, key inflammatory drivers of DKD. This was a large prospective three-cohort study that identified a novel and extremely robust circulating signature (KRIS) associated with risk of ESRD in diabetes. Our pilot study points to the data-driven connection between circulating KRIS and urinary profiles of the Complement pathway. Our hypothesis is that the Complement involvement in the kidney is a downstream effect of the systemic inflammatory processes mediating an increased DKD risk. The overarching goal of this proposal is to provide a high-resolution view of the involvement of the Complement proteome in progressive diabetic kidney disease. Aim 1 will comprehensively evaluate the etiological role of the urinary Complement proteome in progressive DKD leading to ESRD. This evaluation will leverage a prospective two-cohort population of Joslin Kidney Study (JKS) participants with an overt DKD at baseline followed for 10 years (primary outcome – incident ESRD). Measurements will utilize an aptamer proteomic technology (SOMAscan). Aim 2 will extend generalizability of the urinary Complement proteome to earlier DKD stages. The proposed study will be conducted in participants of the Preventing Early Renal Loss (PERL) clinical trial with predominantly normal renal function at baseline followed for 3 years (primary outcome - renal slope). Aim 3 proposes to gain direct insight into the intra-renal Complement proteome by targeted and untargeted protein studies in diabetic kidney tissue (Susztaklab Biobank). This project focuses on a significant public health problem, leverages the progressiveness of the disease, employs an innovative proteomic technology and stems from strong preliminary data. Advances in this project will pinpoint missing key components of DKD etiology, thereby accelerating drug development strategies for patients with diabetes.

项目概要/摘要 迫切需要确定糖尿病肾病 (DKD) 的新机制，从而提供靶点 以获得新的干预措施。慢性炎症是一种可能的机制。 我们最近发表的研究利用非靶向高通量适体蛋白质组学为这一问题提供了新的线索 DKD 的特定关键炎症驱动因素。这是一项大型前瞻性三队列研究，确定了 新颖且极其强大的循环特征（KRIS）与糖尿病 ESRD 风险相关。 我们的试点研究指出循环 KRIS 和尿液特征之间存在数据驱动的联系 补体途径。我们的假设是补体参与肾脏是下游 全身炎症过程的影响介导 DKD 风险增加。 该提案的总体目标是提供有关参与的高分辨率视图 补充进行性糖尿病肾病中的蛋白质组。 目标 1 将全面评估尿补体蛋白质组在进行性进展性疾病中的病因学作用 DKD 导致 ESRD。该评估将利用 Joslin 肾脏研究的前瞻性两队列人群 (JKS) 对基线患有明显 DKD 的参与者进行了 10 年的随访（主要结果 - 事件 ESRD）。 测量将利用适体蛋白质组学技术 (SOMAscan)。 目标 2 将尿补体蛋白质组的普适性扩展到早期 DKD 阶段。拟议的 研究将在预防早期肾功能丧失 (PERL) 临床试验的参与者中进行 基线肾功能基本正常，随访 3 年（主要结果 - 肾斜率）。 目标 3 提出通过有针对性和无针对性的方法直接了解肾内补体蛋白质组 糖尿病肾组织的蛋白质研究（Susztaklab Biobank）。 该项目重点关注重大公共卫生问题，利用疾病的进展性， 采用创新的蛋白质组技术并源自强大的初步数据。该项目的进展 将查明 DKD 病因学缺失的关键组成部分，从而加速针对 DKD 的药物开发策略 糖尿病患者。