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

• 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
• 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

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.

项目摘要/摘要 该项目将建立一个新的肾脏活检队列，以表征分子，形态和代谢 1型糖尿病（T1D）现代临床过程中糖尿病肾病（DKD）的特征。地标 肾脏活检研究增强了我们对DKD发病机理的理解。但是，进步 连续的葡萄糖监测和自动胰岛素输送已改变糖尿病管理，并改变 T1D中DKD的临床课程。此外，分子方法的创新询问肾脏组织，例如 单细胞RNA测序（SCRNA-SEQ），允许在不以前的分辨率上表征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 缺氧是T1D中DKD发展的中心代谢途径。我们将通过 创建一个独特的新纵向肾脏活检队列（n = 100），跨越了T1D的关键持续时间 DKD启动和进步（5 - 30年）并利用我们现有的先锋活检队列（n = 30）。 我们现有的健康对照组（n = 20），肾脏将提供规范性肾脏活检数据 精密医学项目（KPMP）和额外的活肾脏供体活检。我们将实施最新 ART分子（SCRNA-SEQ）和肾脏组织和严格代谢的形态学询问 表型。具体而言，我们的目的是：（1）在整个过程中定义肾脏能量和缺氧的差异 t1d; （2）缺氧的转录组特征与结构病变和临床 进步DKD的表现； （3）探索扰动肾脏能量学的机械相关性 在具有重复肾脏活检的T1D参与者子集中的缺氧和缺氧。这项工作将有助于定义 DKD中扰动能量和缺氧的作用以及肾脏的风险因素和后果 T1D中的缺氧。这项研究还将生成一个有价值的数据，生物样本和肾脏组织的宝贵存储库 通过KPMP平台公开对T1D中的DKD进行进一步分析。