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

项目总结/摘要 目前迫切需要确定糖尿病肾病（DKD）的新机制， 新的干预措施。慢性炎症是一种可能的机制。 使用非靶向高通量适体蛋白质组学，我们最近发表的研究揭示了 DKD的特异性关键炎症驱动因素。这是一项大型前瞻性三队列研究， 与糖尿病患者ESRD风险相关的一种新型且非常稳健的循环特征（KRIS）。 我们的初步研究指出，数据驱动的循环KRIS和尿液之间的联系， 补体途径。我们的假设是，肾脏中的补体参与是一个下游过程， 介导DKD风险增加的全身炎症过程的影响。 该提案的总体目标是提供有关参与的高分辨率视图 进行性糖尿病肾病中的补体蛋白质组。 目的1全面评价尿补体蛋白质组在进展性肾小球肾炎病因学中的作用 DKD导致ESRD。本评价将利用Joslin肾脏研究的前瞻性两队列人群 (JKS)基线时有明显DKD的参与者随访10年（主要结局-事件ESRD）。 测量将利用适体蛋白质组学技术（SOMAscan）。 目的2将尿补体蛋白质组的普遍性扩展到早期DKD阶段。拟议 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， 基线时肾功能主要正常，随访3年（主要结局-肾斜率）。 目的3提出通过靶向和非靶向的蛋白质组分析， 糖尿病肾组织中的蛋白质研究（Susztaklab Biobank）。 该项目关注一个重大的公共卫生问题，利用疾病的进展， 采用了创新的蛋白质组学技术，并源于强大的初步数据。该项目的进展 将查明DKD病因学中缺失的关键成分，从而加速药物开发策略， 糖尿病患者。

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.