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

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)现代临床病程中糖尿病肾病(DKD)的特点。地标 肾活检研究加深了我们对DKD发病机制的认识。然而，在这方面的进展 持续的血糖监测和自动化的胰岛素输送改变了糖尿病的管理和 弥漫性肾病在T1D的临床病程。此外，询问肾组织的分子方法的创新，例如 单细胞RNA测序(scRNA-seq)，允许以以前没有的分辨率来表征DKD 有可能。根据已发表的工作和我们的初步数据，我们假设扰乱肾脏能量学 低氧是T1D时DKD发生的中心代谢途径。我们将通过以下方式验证这一假设 创建一个独特的新的纵向肾活检队列(N=100)，跨越T1D的关键持续时间 其中DKD启动和进展(5-30年)，并利用我们现有的先锋活检队列(N=30)。 规范的肾脏活检数据将来自我们现有的健康对照队列(N=20)，肾脏 精准医学项目(KPMP)，以及额外的活体肾脏捐赠者活检。我们将实施国情咨文 肾组织的ART分子(scRNA-seq)和形态计量学询问与严格代谢 表型鉴定。具体地说，我们的目标是：(1)确定肾脏能量和缺氧过程中的差异 T1D；(2)低氧转录特征与结构损害和临床的相关性测试 进展性DKD的表现；以及(3)探讨扰动肾脏能量学的机制相关性。 以及重复肾活检的T1D参与者的子集内的低氧。这项工作将有助于定义 扰动能量和低氧在DKD中的作用以及肾脏的危险因素和后果 T1D缺氧组。这项研究还将产生一个有价值的数据、生物样本和肾脏组织的存储库 通过KPMP平台公开提供的T1D中对DKD的进一步分析。

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.