Proteolytic Regulation of Podocyte Function by Cathepsin L

组织蛋白酶 L 对足细胞功能的蛋白水解调节

基本信息

  • 批准号:
    7671063
  • 负责人:
  • 金额:
    $ 14.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2006
  • 资助国家:
    美国
  • 起止时间:
    2006-08-15 至 2011-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): About 20 million Americans have kidney disease. The number of people diagnosed with kidney disease has doubled each decade for the last two decades impacting on human suffering and enormous Medicare costs imposed by end-stage renal failure. Renal ultrafiltration is located within the renal glomerulus and performed by highly specialized podocyte cells. Podocyte foot processes (FPs) and the interposed slit diaphragms (SDs) cover the outer aspect of the glomerular filtration barrier and form a final barrier to protein loss. Damage of podocytes results in proteinuria and may lead to progressive decline of renal function. It is therefore in the interest of the public health to define the regulation of podocyte structure and function at the cellular and molecular levels and identify molecular targets involved in early structural changes leading to podocyte damage and the development of proteinuria. We have made the novel finding that cathepsin L enzyme is present within the cytoplasm of podocytes during nephrotic syndrome and cleaves CD2AP, an important SD protein. Cathepsin L is a lysosomal protease that has a broad biological significance such as intracellular protein degradation, activation of enzyme precursors, and tumor invasion. Normally located in lysosomes, cathepsin L can be found in the cytoplasm or can be secreted under certain conditions. We have developed a novel murine model of transient nephrotic syndrome that shares key features with human nephrotic syndrome which allows us to delineate proteolytic processes in podocytes resulting from the induction of cathepsin L. We propose 3 Specific Aims to unravel the function of extralysosomal cathepsin L expression and activity in podocytes. In the first Specific Aim, we propose to analyze the course and severity of proteinuria in mice lacking cathepsin L and how the lack of this enzyme affects CD2AP binding interactions with other SD proteins. We will then test the hypothesis in detail that the SD protein CD2AP is a proteolytic target protein of cathepsin L and explore the cell-junction stability of cathepsin L cleavage resistant CD2AP mutants (Specific Aim 2). In Specifc Aim 3, we will address the biological significance of cleaved CD2AP fragments and analyse the effects of such peptides on the actin based lysosomal degradome using organellar proteomics. The proposed role of proteolytic processing of podocyte structural and regulatory proteins during nephrotic syndrome represents a novel concept in the molecular work-up of proteinuria. If our hypothesis is correct, our work will have broad significance for the basic understanding of glomerular pathology e.g. the mechanism of podocyte FP effacement. Uncovering the role of podocyte proteolysis will help to develop novel pharmaco-therapeutics (such as cathepsin L resistant CD2AP mutants or small molecules blocking CD2AP cleavage) to tackle proteinuria and progression of glomerular disease.
描述(申请人提供):约有2000万美国人患有肾脏疾病。在过去20年里,被诊断患有肾脏疾病的人数每十年翻一番,这对人类的痛苦和终末期肾功能衰竭带来的巨额医疗保险成本造成了影响。肾超滤位于肾小球内,由高度特化的足细胞执行。足细胞足突(FP)和夹缝隔膜(SD)覆盖在肾小球滤过屏障的外部,形成阻止蛋白质丢失的最终屏障。足细胞受损会导致蛋白尿,并可能导致肾功能进行性下降。因此,在细胞和分子水平上确定足细胞结构和功能的调节,并确定与导致足细胞损伤和蛋白尿发展的早期结构变化有关的分子靶点,符合公众健康的利益。我们的新发现是,在肾病综合征期间,组织蛋白酶L酶存在于足细胞的胞浆中,并裂解了一个重要的SD蛋白CD2AP。组织蛋白酶L是一种溶酶体蛋白水解酶,具有细胞内蛋白降解、酶前体激活、肿瘤侵袭等广泛的生物学意义。组织蛋白酶L通常位于溶酶体中,在细胞质中也可以发现,也可以在一定条件下分泌。我们建立了一种新的小鼠短暂性肾病综合征模型,该模型与人类肾病综合征具有相同的关键特征,该模型允许我们描述由组织蛋白酶L诱导的足细胞蛋白分解过程。我们提出了3个特异性靶点来揭示解体外组织蛋白酶L在足细胞中的表达和活性。在第一个特定目标中,我们建议分析缺乏组织蛋白酶L的小鼠蛋白尿的过程和严重程度,以及该酶的缺乏如何影响CD2AP与其他SD蛋白的结合作用。然后,我们将详细检验这一假设,即SD蛋白CD2AP是组织蛋白酶L的蛋白水解靶蛋白,并探索组织蛋白酶L抗切割CD2AP突变体的细胞连接稳定性(特定目标2)。在特定的目标3中,我们将讨论切割的CD2AP片段的生物学意义,并利用细胞器蛋白质组学分析这些肽对基于肌动蛋白的溶酶体降解组的影响。在肾病综合征中足细胞结构和调节蛋白的蛋白水解性加工的提出代表了蛋白尿分子研究的一个新概念。如果我们的假设是正确的,我们的工作将对肾小球病理的基本理解,例如足细胞FP消失的机制具有广泛的意义。揭示足细胞蛋白分解的作用将有助于开发新的药物疗法(如组织蛋白酶L抗性的CD2AP突变体或阻断CD2AP裂解的小分子)来治疗蛋白尿和肾小球疾病的进展。

项目成果

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Jochen Reiser其他文献

Jochen Reiser的其他文献

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{{ truncateString('Jochen Reiser', 18)}}的其他基金

Role of proteolytic suPAR fragment in insulin dependent diabetes and kidney disease
蛋白水解suPAR片段在胰岛素依赖性糖尿病和肾脏疾病中的作用
  • 批准号:
    10654224
  • 财政年份:
    2023
  • 资助金额:
    $ 14.88万
  • 项目类别:
suPAR and renal fibrosis
suPAR与肾纤维化
  • 批准号:
    10412048
  • 财政年份:
    2020
  • 资助金额:
    $ 14.88万
  • 项目类别:
suPAR and renal fibrosis
suPAR与肾纤维化
  • 批准号:
    10035085
  • 财政年份:
    2020
  • 资助金额:
    $ 14.88万
  • 项目类别:
suPAR and renal fibrosis
suPAR与肾纤维化
  • 批准号:
    10620226
  • 财政年份:
    2020
  • 资助金额:
    $ 14.88万
  • 项目类别:
suPAR and renal fibrosis
suPAR与肾纤维化
  • 批准号:
    10220027
  • 财政年份:
    2020
  • 资助金额:
    $ 14.88万
  • 项目类别:
The KIDCOV Study: Assessment of Kidney Injury and Associated Risk Factors for SARS-CoV-2
KIDCOV 研究:评估 SARS-CoV-2 肾损伤及相关风险因素
  • 批准号:
    10216618
  • 财政年份:
    2017
  • 资助金额:
    $ 14.88万
  • 项目类别:
CD40 autoantibody and FSGS recurrence
CD40自身抗体与FSGS复发
  • 批准号:
    9912137
  • 财政年份:
    2017
  • 资助金额:
    $ 14.88万
  • 项目类别:
CD40 autoantibody and FSGS recurrence
CD40自身抗体与FSGS复发
  • 批准号:
    9333947
  • 财政年份:
    2017
  • 资助金额:
    $ 14.88万
  • 项目类别:
A Humanized Mouse Model of FSGS
FSGS 人源化小鼠模型
  • 批准号:
    9070608
  • 财政年份:
    2015
  • 资助金额:
    $ 14.88万
  • 项目类别:
Role of Circulating suPAR in FSGS
循环 suPAR 在 FSGS 中的作用
  • 批准号:
    8882417
  • 财政年份:
    2013
  • 资助金额:
    $ 14.88万
  • 项目类别:

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