Defining the molecular landscape of hyperfiltration-mediated glomerular injury using kidney allografts as a model system

使用同种异体肾移植物作为模型系统定义超滤介导的肾小球损伤的分子景观

• 批准号: 10543150
• 负责人: Abhijit S Naik
• 金额: $ 19.22万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543150
• 关键词: Acceleration; Allografting; Animal Model; Area; Automobile Driving; Bioinformatics; Biological Assay; Biological Models; Biopsy; Cells; Characteristics; Chronic Kidney Failure; Core Biopsy; Data; Development; Diabetes Mellitus; Disease; Disease Pathway; Disease Progression; EDN1 gene; Enrollment; Epidemic; Etiology; Exposure to; Failure; Filtration; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Goals; Histology; Human; Hydrostatic Pressure; IGF1 gene; Immunohistochemistry; In Situ Hybridization; Infection; Injury; Insulin-Like Growth-Factor-Binding Proteins; Integrin alpha3beta1; KDR gene; Kidney; Kidney Diseases; Kidney Transplantation; Knowledge; Ligands; Link; Longevity; Measurement; Measures; Mediating; Modeling; Molecular; Monitor; Morbidity - disease rate; Nephrons; Obesity; Outcome; Overlapping Genes; Pathogenesis; Pima Indian; Process; Public Health; Recurrence; Renal glomerular disease; Research; Research Personnel; Role; Side; Specificity; Stress; Systems Biology; Technology; Testing; Time; Training; Transcript; Transplantation; Urine; VEGFA gene; cohort; diabetic; diabetic patient; differential expression; genetic signature; glomerular basement membrane; graft function; human model; improved; innovation; insight; kidney allograft; living kidney donor; mortality; new therapeutic target; non-invasive monitor; podocyte; post-transplant; receptor; renal damage; response; single-cell RNA sequencing; targeted treatment; transcriptome; transcriptome sequencing; transcriptomics; validation studies

ABSTRACT: Long-term kidney allograft survival has not improved significantly over the last two decades. Accumulating data supports the hypothesis that progressive glomerular disease drives late kidney allograft failure, with hyper- filtration mediated glomerular injury being a putative driver. In addition, hyperfiltration is implicated in the progres- sion of kidney diseases such as in diabetes and obesity, both of which have reached epidemic proportions. How- ever, the molecular underpinnings of this shared mechanism of kidney disease progression remain unclear and forms the scientific basis of this proposal. My long-term goal is to understand disease mechanisms driving late allograft loss, with a focus on prolonging allograft lifespan. The overall objective of this application is to elucidate the molecular mechanisms by which hyperfiltration initiates and drives the podocyte detachment process in kidney allografts. We will also test whether parallel mechanisms are operating in an independent cohort of hyperfiltering diabetic patients. Towards achieving this objective my central hypothesis is that hyperfiltration leads to a characteristic molec- ular footprint in the glomerulus that drives podocyte stress and accelerated detachment. To identify the underlying molecular mechanism of hyperfiltration, a combination of bulk- and single cell RNA-sequencing technology will be used to identify glomerular cell-specific gene signatures as well as interactions between cells associated with the glomerular basement membrane that are known to drive podocyte detachment. To enable non-invasive mon- itoring of podocyte loss, we will use urine pellet podocyte detachment assays and measure hyperfiltration using filtration fraction studies. We will test the central hypothesis using three specific aims: Aim 1. Define the glomerular transcriptional response to hyperfiltration. Aim 2. Define the glomerular transcriptional profile that drives accelerated podocyte detachment and identify the effect of hyperfiltration on this relationship. Aim 3: Define the relationship of allograft hyperfiltration with podocyte stress and detachment. The research is innovative as it uses human kidney allografts as a model system to focus on hyperfiltration as a common mechanism of kidney disease progression analyzed by state-of-the-art technologies. The proposed research is significant as the identification of shared pathways of disease progression between kidney diseases could lead to the development of novel targeted therapeutic agents and non-invasive monitoring strategies. Ulti- mately, such knowledge will be crucial to slow down kidney disease progression regardless of its etiology.

抽象的： 在过去的二十年中，长期的肾脏同种异体生存率并未显着改善。累积 数据支持以下假设：进行性肾小球疾病驱动后期肾脏同种异体移植失败，并具有多个 过滤介导的肾小球损伤是推定的驱动器。另外，过滤与前期有关 肾脏疾病（例如糖尿病和肥胖症）的疾病，两者都达到了流行比例。如何- 曾经，这种肾脏疾病进展的共享机制的分子基础尚不清楚，并且 构成了该提议的科学基础。 我的长期目标是了解驱动晚期同种异体移植后期丧失的疾病机制，重点是延长 同种异体移植寿命。该应用的总体目的是阐明分子机制 过滤启动并驱动肾脏同种异体移植物的足细胞脱离过程。我们还将测试是否 平行机制在独立的糖尿病患者的独立队列中运行。 为了实现这一目标，我的中心假设是过滤导致特征性分子 肾小球中的Ular足迹驱动足细胞应力和加速脱离。识别基础 超滤的分子机制，散装和单细胞RNA测序技术的组合将 用于识别肾小球细胞特异性基因特异性基因特异性以及与与之相关的细胞之间的相互作用 已知可以驱动足细胞脱离的肾小球基底膜。为了实现非侵入性mon- 迭代足细胞损失，我们将使用尿液颗粒足细胞分离测定法，并使用 过滤分数研究。我们将使用三个特定目的测试中心假设： AIM 1。定义肾小球转录响应对过滤。 AIM 2。定义肾小球的转录轮廓，该轮廓曲线驱动加速的足细胞脱离并识别 过滤对这种关系的影响。 目标3：定义同种异体移植过滤与足细胞应力和脱离的关系。 这项研究具有创新性，因为它使用人类肾脏同种异体移植作为模型系统来专注于过滤 作为通过最先进技术分析的肾脏疾病进展的常见机制。提议 研究意义重大，因为鉴定肾脏疾病之间疾病进展的共同途径 可能导致新型靶向治疗剂和非侵入性监测策略的发展。终极 几乎，这种知识对于减慢肾脏疾病进展至关重要，无论其病因如何。