The Glomerular Podocyte

描述（由申请人提供）：我们将测试相对于 足细胞消耗与肾小球面积有关， 肾小球硬化（GS）。GS是肾小球瘢痕形成过程， 与导致糖尿病患者终末期肾病的肾功能进行性丧失相关， 高血压，局灶节段性GS（FSGS）和遗传性和免疫性形式的 GS.这些条件加在一起约占90%的ESRD，主要 发病率/死亡率和每年超过100亿美元的成本， 我们清静一点.随着人口老龄化，ESRD正在接近流行病的比例。我们 从尸检报告中得知，GS发生的频率在40岁以上 岁的GS被充分证明与足细胞损伤有关。新 来自实验动物和糖尿病患者的数据强化了这一概念 肾小球面积和足细胞数量之间的关系 很危险每个分化的足细胞都有有限的分裂能力， 覆盖更大面积的GBM。我们假设，如果一个阈值 如果超过肾小球足细胞面积（GAPP），则将产生GS。我们将 通过开发小鼠转基因模型来测试这一假设， 足细胞消耗可以随意测定，并测量结果GS （目标1）。在目标2中，我们将使用大鼠模型来检验以下假设： 足细胞数量与肾小球面积的关系决定了GS的发生， 衰老和肾衰竭目的3将评估人类肾活检， 建立年龄、性别和种族的GAPP正常范围，并确定是否 在人类中与GS相关的疾病具有类似的相对足细胞消耗。 足细胞耗竭作为一种主要机制的鉴定 肾小球硬化症将是朝着改善发展的重要一步。 预防疾病进展的新策略、新的监测策略和新的 治疗肾小球硬化症

DESCRIPTION (provided by applicant): We will test the hypothesis that relative podocyte depletion in relation to glomerular area to be served causes glomeruloscierosis (GS). GS is the glomerular scarring process that is associated with progressive loss of renal function leading to ESRD in diabetic, hypertensive, Focal Segmental GS (FSGS) and in hereditary and immune forms of GS. Together these conditions account for about 90 percent of ESRD, major morbidity/mortality and a cost of more than 10 billion dollars per year in the US alone. ESRD is approaching epidemic proportions as the population ages. We know from autopsy reports that GS occurs with increasing frequency above 40 years of age. GS is well documented to be associated with podocyte injury. New data from experimental animals and diabetic man have reinforced the concept that it is the relationship between glomerular area and podocyte count that is critical. Each differentiated podocyte has limited capacity to divide and to cover an increased area of GBM. We hypothesize that if a threshold value for Glomerular Area Per Podocyte (GAPP) is exceeded then GS will result. We will test this hypothesis by developing a mouse transgenic model where degree of podocyte depletion can be determined at will and resu;lting GS measured directly (Aim 1). In Aim 2 we will use rat models to test the hypothesis that podocyte number in relation to glomerular area determines the onset of GS in aging and renal depletion. Aim 3 will evaluate human renal biopsies to establish normal ranges GAPP for age, sex and race and to determine whether diseases associated with GS in man have similar relative podocyte depletion. The identification of podocyte depletion as a major mechanism underlying glomerulosclerosis will be an important step towards development of improved strategies for prevention of progression, new monitoring strategies and new treatments for glomerulosclerosis.