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: 10211654
• 负责人: Abhijit S Naik
• 金额: $ 19.34万
• 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/10211654
• 关键词: 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; Lead; Ligands; Link; Longevity; Measurement; Measures; Mediating; Modeling; Molecular; Monitor; Morbidity - disease rate; Nephrons; Obesity; Outcome; Overlapping Genes; Partner in relationship; 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; Vascular Endothelial Growth Factors; 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.

摘要： 在过去的二十年中，移植肾的长期存活率并没有显著改善。积累 数据支持进行性肾小球疾病导致晚期同种异体肾移植衰竭的假设，并伴有高... 滤过介导的肾小球损伤是可能的驱动因素。此外，超滤参与了进展- 肾脏疾病，如糖尿病和肥胖症，这两种疾病都达到了流行的程度。怎么- 迄今为止，这种肾脏疾病进展的共同机制的分子基础仍然不清楚。 构成了这一提议的科学基础。 我的长期目标是了解导致晚期同种异体移植物丢失的疾病机制，重点是延长 同种异体移植的寿命。这一应用的总体目标是阐明其分子机制 在移植肾中，高滤过启动并驱动足细胞脱离过程。我们还将测试 平行机制在一个独立的高滤过糖尿病患者队列中运行。 为了实现这一目标，我的中心假设是，超滤会导致一种特有的分子-- 肾小球中的小球足迹，导致足细胞应激和加速脱离。要识别潜在的 超滤的分子机制，结合散体和单细胞RNA测序技术将 用于识别肾小球细胞特异的基因特征以及与 肾小球基底膜是已知的驱动足细胞脱离的物质。要启用非侵入式监控- 对于足细胞丢失，我们将使用尿粒体足细胞分离分析，并使用 过滤分数研究。我们将使用三个具体目标来检验中心假设： 目的1.明确肾小球对高滤过的转录反应。 目标2：定义驱动加速足细胞脱离的肾小球转录图谱，并确定 超滤对这种关系的影响。 目的3：明确同种异体移植物高滤过与足细胞应激和脱离的关系。 这项研究具有创新性，因为它以人肾移植为模型系统，专注于超滤。 作为肾脏疾病进展的一种常见机制，由最先进的技术分析。建议数 随着肾脏疾病之间疾病进展的共同途径的确定，研究具有重要意义 可能导致新的靶向治疗剂和非侵入性监测策略的开发。多- 更重要的是，这些知识将是减缓肾脏疾病进展的关键，无论其病因如何。