Molecular signatures of diabetic kidney disease

 描述（由申请人提供）：糖尿病肾病（DKD）发生在30-40%的2型糖尿病患者中。患有糖尿病和估计肾小球滤过率降低（eGFR <60 ml/min/1.73m2）的人患终末期肾病（ESRD）以及心血管疾病和死亡的风险特别高。尽管强化血糖控制和肾素血管紧张素系统（RAS）抑制，进展为ESRD和死亡的比率仍然很高。开发针对该DKD阶段的新疗法需要更深入地了解导致DKD进展的机制，特别是在疾病的该阶段。该提案的总体目标是确定与2型糖尿病从eGFR降低进展为ESRD相关的生物学途径。我们建议利用最先进的靶向定量蛋白质组学平台，在eGFR降低进展为ESRD或eGFR下降50%之前，对来自12种生物学上有希望的候选途径的179种蛋白质的表达进行定量。选择这些途径是因为它们得到了DKD动物模型的广泛支持以及参与晚期人类DKD的证据，但之前尚未在人类DKD的该阶段进行评价。使用我们最近完成的人类选择性反应监测图谱（一个能够对20，300种人类蛋白质进行定量蛋白质组学的肽库）中的免疫测定和定量靶向测定，我们检查了来自上述12种候选途径中的4种的28种蛋白质的尿液浓度。我们的初步数据表明，这些蛋白质中有25种的浓度明显异常，这与明显DKD时其相应途径的预期失调一致。我们假设12个靶向通路中的一个亚组在eGFR降低时失调，并与进展为ESRD相关。为了验证这一假设，我们提出了一个病例对照研究嵌套在2型糖尿病亚队列的慢性肾功能不全队列（CRIC）研究，随后在西雅图肾脏研究（SKS）的验证。我们将在随访期间比较患有糖尿病和eGFR降低的CRIC参与者中来自12个关键DKD途径的179种蛋白质的尿液浓度，这些参与者在随访期间进展或不进展为事件ESRD或eGFR损失50%。我们将使用这些新的测量和相应的临床数据来测试以下假设：目的1。确定在糖尿病和eGFR降低的人群中发生改变并与DKD进展相关的蛋白质和相应途径。目标2.在第二个队列（西雅图肾脏研究（SKS））中验证CRIC研究（目标1）中与DKD进展相关的蛋白质和途径。

 DESCRIPTION (provided by applicant): Diabetic kidney disease (DKD) occurs in 30-40% of people with type 2 diabetes. People with diabetes and reduced estimated glomerular filtration rate (eGFR <60 ml/min/1.73m2) are at particularly high risk of end-stage renal disease (ESRD) as well as cardiovascular disease and death. Despite intensive glycemic control and renin angiotensin system (RAS) inhibition, the rates of progression to ESRD and death remain high. Development of new therapies targeting this DKD stage requires greater understanding of the mechanisms causing DKD progression, particularly at this stage of disease. The overall goal of this proposal is to identify the biologic pathways that are associated with progression from reduced eGFR to ESRD in type 2 diabetes. We propose to utilize a state-of-the-art, targeted, quantitative proteomics platform to quantify expression of 179 proteins from 12 biologically promising candidate pathways prior to progression from reduced eGFR to incident ESRD or 50% drop in eGFR. These pathways are selected because they have extensive support from DKD animal models as well as evidence of involvement in advanced human DKD, but have not been previously evaluated at this stage of human DKD. Using immunoassays and quantitative targeted assays from our recently completed Human Selected Reaction Monitoring Atlas (a library of peptides enabling quantitative proteomics for 20,300 human proteins), we examined urine concentration of 28 proteins from four of the above 12 candidate pathways. Our preliminary data suggests that the concentrations of 25 of these proteins are markedly abnormal, consistent with expected dysregulation of their corresponding pathways at the time of overt DKD. We hypothesize that a subset of the 12 targeted pathways are dysregulated at the time of reduced eGFR and are associated with progression to ESRD. To test this hypothesis, we propose a case-control study nested within a type 2 diabetes sub cohort of the Chronic Renal Insufficiency Cohort (CRIC) Study, with subsequent validation in the Seattle Kidney Study (SKS). We will compare urine concentration of 179 proteins from 12 key DKD pathways in CRIC participants with diabetes and reduced eGFR who do or do not progress to incident ESRD or 50% loss of eGFR during follow-up. We will use these novel measurements and the corresponding clinical data to test the following hypotheses: Aim 1. To identify the proteins and corresponding pathways which are altered in people with diabetes and reduced eGFR and are associated with DKD progression. Aim 2. To validate the proteins and pathways associated with DKD progression in the CRIC study (Aim 1) in a second cohort, the Seattle Kidney Study (SKS).