Pathogenesis of kidney disease in type 1 diabetes: a modern kidney biopsy cohort

1 型糖尿病肾脏疾病的发病机制：现代肾活检队列

基本信息

批准号：
10627851
负责人：
Petter M Bjornstad
金额：
$ 59.12万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-23 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627851
关键词：
Adult Albuminuria Biopsy Cessation of life Clinical Closure by clamp Complex Continuous Glucose Monitor Cross-Sectional Studies Data Development Diabetic Nephropathy Dialysis procedure Disease Outcome Dual-Energy X-Ray Absorptiometry Energy Metabolism Exhibits FRAP1 gene Genetic Transcription Glomerular Filtration Rate Glucose Clamp Goals HIF1A gene Hyperglycemia Hyperinsulinism Hypoxia Hypoxia Inducible Factor Impairment Incidence Individual Inflammation Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Intra-abdominal Iohexol K ATPase Kidney Kidney Diseases Kidney Failure Kidney Transplantation Knowledge Lesion Living Donors Magnetic Resonance Imaging Measurement Measures Mediating Metabolic Metabolic Pathway Metabolism Methods Mitochondria Modernization Molecular Molecular Profiling Noise Obesity Oxygen Participant Pathogenesis Pathologic Performance Persons Plasma Publishing Renal Plasma Flow Residual state Resolution Risk Risk Factors Role Signal Transduction Sodium Structure System Testing Tissues Tubular formation United States Up-Regulation Urine Work Youth abdominal fat absorption adenylate kinase cardiovascular disorder risk cell injury clinical phenotype cohort data repository diabetes management disorder prevention effective therapy follow-up glycemic control improved innovation insulin sensitivity interstitial kidney biopsy living kidney donor metabolic phenotype metabolomics mitochondrial dysfunction modifiable risk novel precision medicine premature prevent renal hypoxia single-cell RNA sequencing stem targeted treatment transcriptomics

项目摘要

Project Summary/Abstract This project will build a new kidney biopsy cohort to characterize the molecular, morphometric, and metabolic features of diabetic kidney disease (DKD) over the modern clinical course of type 1 diabetes (T1D). Landmark kidney biopsy studies have enhanced our understanding of DKD pathogenesis. However, advances in continuous glucose monitoring and automated insulin delivery have changed diabetes management and the clinical course of DKD in T1D. Moreover, innovation in molecular methods to interrogate kidney tissue, such as single-cell RNA sequencing (scRNA-seq), allows characterization of DKD at a resolution not previously possible. Based on published work and our preliminary data, we hypothesize that perturbed kidney energetics and hypoxia are central metabolic pathways in the development of DKD in T1D. We will test this hypothesis by creating a unique new longitudinal kidney biopsy cohort (N=100) spanning the critical duration of T1D over which DKD initiates and progresses (5-30 years) and leveraging our existing vanguard biopsy cohort (N=30). Normative kidney biopsy data will be provided from our existing cohort of healthy controls (N=20), the Kidney Precision Medicine Project (KPMP), and additional living kidney donor biopsies. We will implement state-of- the-art molecular (scRNA-seq) and morphometric interrogation of kidney tissue and rigorous metabolic phenotyping. Specifically, we aim to: (1) define differences in kidney energetics and hypoxia over the course of T1D; (2) test associations of the transcriptomic signatures of hypoxia with the structural lesions and clinical manifestations of progressive DKD; and (3) explore the mechanistic correlates of perturbed kidney energetics and hypoxia within a subset of participants with T1D with repeat kidney biopsies. This work will help define the role of perturbed energetics and hypoxia in DKD as well as risk factors for and consequences of kidney hypoxia in T1D. This study will also generate a valuable repository of data, biosamples, and kidney tissue for further analysis of DKD in T1D, made publicly available through the KPMP platform.

项目概要/摘要该项目将建立一个新的肾活检队列来表征分子、形态和代谢糖尿病肾病 (DKD) 在现代 1 型糖尿病 (T1D) 临床病程中的特点。地标肾活检研究增强了我们对 DKD 发病机制的了解。然而，在连续血糖监测和自动胰岛素输送改变了糖尿病管理和 T1D 中 DKD 的临床过程。此外，研究肾脏组织的分子方法的创新，例如单细胞 RNA 测序 (scRNA-seq) 能够以前所未有的分辨率表征 DKD 可能的。根据已发表的工作和我们的初步数据，我们假设肾脏能量学受到干扰缺氧和缺氧是 T1D 中 DKD 发展的中心代谢途径。我们将通过以下方式检验这个假设创建一个独特的新纵向肾活检队列 (N=100)，跨越 T1D 的关键持续时间 DKD 发起并取得进展（5-30 年），并利用我们现有的先锋活检队列 (N=30)。规范的肾活检数据将从我们现有的健康对照队列 (N=20) 中提供，即肾脏精准医学项目 (KPMP) 和其他活体肾脏捐赠者活检。我们将实施状态对肾组织和严格代谢进行最先进的分子 (scRNA-seq) 和形态测量分析表型分析。具体来说，我们的目标是：（1）定义肾脏能量学和缺氧过程中的差异 T1D； (2) 测试缺氧转录组特征与结构性病变和临床的关联进行性 DKD 的表现； (3) 探索肾脏能量学紊乱的机制相关性部分患有 T1D 的参与者重复进行肾活检，导致缺氧。这项工作将有助于定义能量紊乱和缺氧在 DKD 中的作用以及肾病的危险因素和后果 T1D 缺氧。这项研究还将生成一个有价值的数据、生物样本和肾组织存储库，用于 T1D 中 DKD 的进一步分析，通过 KPMP 平台公开发布。