Podocyte Markers in Human Glomerular Diseases

人类肾小球疾病中的足细胞标志物

基本信息

批准号：
9137679
负责人：
ROGER Charles WIGGINS
金额：
$ 23.25万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-10 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9137679
关键词：
Age Aging Aging-Related Process Allografting Biological Assay Biological Models Biopsy Cell Volumes Clinical Clinical Trials Data Decision Making Development Diabetes Mellitus Disease Elderly End stage renal failure Environment Focal Segmental Glomerulosclerosis Half-Life Health Human Hypertrophy Individual Injury Kidney Kidney Failure Kidney Transplantation Laboratories Life Measurement Measures Messenger RNA Methodology Monitor NPHS2 protein National Institute of Diabetes and Digestive and Kidney Diseases Nephrectomy Normal Range Nuclear Patients Phenotype Population Prevalence Prevention Process Protocols documentation Recurrence Renal glomerular disease Reporting Risk Source Staging Stress Technology Testing Translations Transplantation Treatment Efficacy Urine age related clinical practice density falls glomerulosclerosis graft failure implantation improved outcome insight man new technology novel novel therapeutics podocyte preimplantation prevent tool

项目摘要

DESCRIPTION (provided by applicant): Markers that identify risk for End Stage Kidney Disease (ESKD) and accurately report treatment efficacy will place glomerular diseases into a new paradigm of logical decision-making that improves outcome and efficient testing of new drugs. The Wiggins laboratory (supported by NIDDK) has used model systems to prove that podocyte depletion is the underlying mechanism responsible for progression of glomerular diseases to ESKD, and to demonstrate that urine podocyte mRNA markers non-invasively monitor accelerated podocyte detachment common to all progressive glomerular diseases in man and model systems. We have now developed novel automatable technology that allows high throughput measurement of podocyte density, number per tuft, size and other parameters in routine kidney biopsies. Application of these quantitative approaches to archival human biopsies shows a remarkable age-dependent decrease in podocyte density that can in part explain age-associated kidney failure in man (Aim 1). The kidney transplant setting (where protocol biopsies are routinely done prior to and following transplantation and where patients are closely followed long term) will be used to test the hypotheses that transition from the 2 kidney to the 1 kidney state is associated with hypertrophic podocyte stress that results in accelerated podocyte depletion long term, and that transplant glomerulopathy occurs in those individuals with high level prolonged podocyte depletion (Aim 2). Recurrent FSGS in the allograft will be used as a model system to test the hypothesis that FSGS supervenes when the podocyte density falls below a critical threshold (100 per 106 um3) (Aim 3). The relationship between the rate of podocyte detachment (as measured by the non-invasive urine pellet podocyte marker) and the rate of loss of podocytes from glomeruli (measured morphometrically as the decrease in podocyte number per glomerular tuft and density in relation to glomerular volume) will be defined. The insights developed and principles established will be applicable to prevention of progression in human glomerular diseases.

描述（由适用提供）：确定终阶段肾脏疾病风险（ESKD）和准确报告治疗效率的标记将使肾小球疾病置于逻辑决策的新范式中，从而改善了对新药的结果和有效测试。 The Wiggins laboratory (supported by NIDDK) has used model systems to prove that podocyte deployment is the underlying mechanism responsible for progression of glomerular diseases to ESKD, and to demonstrate that urine podocyte mRNA markers non-invasively monitor accelerated podocyte detachment common to all progressive glomerular diseases in man and model systems.现在，我们开发了新型的自动机技术，可以允许对足细胞密度，每簇数量，大小和常规肾脏活检中的其他参数进行高吞吐量测量。这些定量方法在档案档案中的应用显示，足细胞密度的年龄依赖性下降显着下降，这可以部分解释人类中与年龄相关的肾衰竭（AIM 1）。肾脏移植设置（在移植之前和之后定期进行方案活检以及长期遵守患者的情况）将用于测试从2个肾脏过渡到1肾脏状态的假设，该假说与肥厚的足细胞压力与肥大的足长期和该层次的层次相关的层次均与该层次延伸的人相关，并延伸了该层次的GLLONS级别，并延伸了该级别的层次，并延伸了该级别的过度层次，并延伸了该级别的过度范围。足细胞耗竭（AIM 2）。同种异体移植中的复发性FSG将用作模型系统，以测试当Podocyte密度降至临界阈值以下（每106 UM3 100）时，FSG超过了。足细胞脱离率（通过非侵入性尿液颗粒足细胞标记物测量）与肾小球损失的足细胞损失速率（随着每个肾小球簇和密度的低密度与肾小球量的相对于肾小球量的降低，以形态图测量的形态图测量）。开发的见解和确定的原则将适用于预防人肾小球疾病的进展。