Podocyte Markers in Human Glomerular Diseases

人类肾小球疾病中的足细胞标志物

• 批准号: 8859222
• 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
• 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/8859222
• 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; 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; Outcome; Patients; Pharmaceutical Preparations; 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; insight; man; new technology; novel; podocyte; preimplantation; prevent; public health relevance; tool

 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（由申请人提供）：识别终末期肾病（ESKD）风险并准确报告治疗效果的标记物将把肾小球疾病置于逻辑决策的新范式中，从而改善新药的结果和有效测试。 Wiggins 实验室（由 NIDDK 支持）使用模型系统证明足细胞耗竭是导致肾小球疾病进展为 ESKD 的根本机制，并证明尿液足细胞 mRNA 标记物可无创地监测人类和模型系统中所有进行性肾小球疾病常见的加速足细胞脱离。我们现已开发出新型自动化技术，可在常规肾活检中高通量测量足细胞密度、每簇数量、大小和其他参数。将这些定量方法应用于存档的人类活组织检查表明足细胞密度显着随年龄而下降，这可以部分解释与年龄相关的人类肾衰竭（目标 1）。肾移植环境（移植前和移植后常规进行活检，并且对患者进行长期密切随访）将用于测试以下假设：从第 2 个肾到第 1 个肾状态的转变与肥大性足细胞应激相关，导致足细胞长期加速耗竭，并且移植肾小球病发生在那些长期处于高水平的个体中。 足细胞耗竭（目标 2）。同种异体移植物中复发的 FSGS 将用作模型系统，以检验当足细胞密度低于临界阈值（每 106 um3 100 个）时 FSGS 随之发生的假设（目标 3）。将定义足细胞脱离率（通过非侵入性尿液沉淀足细胞标记物测量）和肾小球足细胞丢失率（通过形态测量测量每个肾小球簇足细胞数量的减少以及与肾小球体积相关的密度）之间的关系。所得出的见解和建立的原则将适用于预防人类肾小球疾病的进展。