Podocyte stress hypertrophy and depletion

足细胞应激肥大和耗竭

• 批准号: 7989856
• 负责人: ROGER Charles WIGGINS
• 金额: $ 7.04万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-17 至 2010-12-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989856
• 关键词: Adult; Affect; Aging; Angiotensin II; Biological Models; Biology; Cell Size; Cells; Child; Cost of Illness; Databases; Diabetes Mellitus; Diagnostic; Diet; Disease; Dose; End stage renal failure; Event; Focal Segmental Glomerulosclerosis; Grant; Human; Hyperplasia; Hypertension; Hypertrophy; Immunoglobulin A; Kidney Diseases; Lead; Lupus; Methods; Minority; Modeling; Morbidity - disease rate; Pathologic; Pathologic Processes; Pathway interactions; Phenotype; Population; Predisposition; Prevalence; Prevention; Process; Rattus; Relative (related person); Renal glomerular disease; Renin-Angiotensin System; Sclerosis; Stress; Testing; Time; Transgenes; Transgenic Model; Transgenic Organisms; Work; base; cell type; diphtheria toxin receptor; driving force; glomerulosclerosis; human FRAP1 protein; human disease; man; mortality; novel; novel strategies; podocyte; prevent; programs; progression marker; response; tool

DESCRIPTION (provided by applicant): Glomerulosclerosis is the common pathologic process responsible for 90% of End Stage Kidney Disease (ESKD) associated with diabetes, hypertension, IgA nephropathy, Focal Segmental Glomerulosclerosis (FSGS), lupus and other glomerular diseases. Together these diseases cost approximately $18 billion per year in the US, and carry high morbidity and mortality. They are increasing in prevalence and are commoner in minority populations. They affect both children and adults, although ESKD is particularly a disease of aging with average onset of ESKD treatment at 64 years. The central hypothesis underlying this work is that glomerulosclerosis is caused by depletion of one of the glomerular cell types, the podocyte. During the prior grant cycle we developed a new transgenic model system in the rat where we can deplete podocytes by an amount and at a time of prior choosing. We show that podocyte depletion does indeed cause all the features of FSGS in a dose-dependant manner. Second we have developed a new method for counting podocytes in glomeruli. Third, we have shown how glomerular enlargement during aging on a high calorie diet causes relative podocyte depletion that predisposes to glomerulosclerosis, and how this can be prevented by calorie restiction. Because we know that hypertension is commonly associated with glomerulosclerosis and progression of glomerulosclerosis to ESKD, these new tools and concepts will be used to test specific hypotheses relevant to human glomerulosclerosis: Aim 1: Podocyte depletion itself causes systemic hypertension and mesangial expansion, an important pathologic component of early glomerulosclerosis in man. Aim 2: Test the hypothesis that limitation of the ability of the podocyte to increase in size makes the glomerulus more susceptible to glomerulosclerosis, while enhancement of podocyte's ability to increase in size prevents glomerulosclerosis, by using transgenes of the mTOR pathway of cell size control to modulate podocyte size. Aim 3: Validate the novel concepts of podocyte alteration in phenotype in response to stress that we have termed "adaptation" and "decompensation" in two rat models of glomerulosclerosis, with the underlying concept that understanding the biology of this process will allow us to develop markers for human podocyte stress as well as new approaches to treat and prevent podocyte stress before it results in loss of podocytes and consequent glomerulosclerosis.

描述（由申请人提供）：肾小球硬化是导致与糖尿病，高血压，IGA肾病，局灶性分段性肾小球硬化症（FSGS），狼疮和其他肾小球疾病相关的90％末期肾脏疾病（ESKD）的常见病理过程。这些疾病在美国每年的损失约为180亿美元，并具有高发病率和死亡率。他们的患病率正在增加，在少数族裔人口中更为常见。它们会影响儿童和成人，尽管ESKD尤其是一种衰老的疾病，而在64岁时的ESKD平均治疗开始。这项工作的基础假设是肾小球硬化是由肾小球细胞类型之一（Podocyte）耗尽引起的。在先前的赠款周期中，我们在大鼠中开发了一个新的转基因模型系统，在该系统中，我们可以在选择的时间内耗尽了足够的足细胞。我们表明，足细胞的耗竭确实确实以剂量依赖性的方式引起了FSG的所有特征。其次，我们开发了一种在肾小球中计数足细胞的新方法。第三，我们已经展示了高热量饮食中衰老过程中的肾小球增大如何导致相对足细胞耗尽，使肾小球硬化症易受到倾向，以及如何通过降低卡路里来预防。 Because we know that hypertension is commonly associated with glomerulosclerosis and progression of glomerulosclerosis to ESKD, these new tools and concepts will be used to test specific hypotheses relevant to human glomerulosclerosis: Aim 1: Podocyte depletion itself causes systemic hypertension and mesangial expansion, an important pathologic component of early glomerulosclerosis in man.目标2：检验以下假设：足细胞增加大小的能力使肾小球更容易受到肾小球硬化的影响，同时增强了Podocyte增加尺寸的能力，可以通过使用细胞尺寸控制的MTOR途径来控制Podocyte尺寸的MTOR途径。目标3：在两种大鼠的肾小球硬化模型中，验证表型中的足细胞改变的新概念，以应对压力，并以此为基础的概念，即理解这一过程的生物学，使我们能够为人类的Podocyte压力和预防损失带来的损失和预防效果的损失，并导致podocyte的损失，并导致Podocyte的损失。肾小球硬化。