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中文摘要
翻译
足细胞耗竭是进行性肾小球硬化和糖尿病肾病的标志。CD2- 相关蛋白(CD2AP)是一种广泛表达的细胞质衔接蛋白, 参与足细胞裂膜蛋白复合物的形成。CD2AP敲除小鼠发生进行性 生命早期肾小球硬化和CD2AP单倍不足与肾小球疾病相关 人类的易感性然而,目前尚不清楚CD2AP功能的丧失如何导致 肾小球硬化在本更新申请中,我们将扩展我们的工作,以检验CD2AP 作为抑制TGF-β的分子开关,促进肾上皮细胞存活 受体I型(Tgfbr 1)/Smad3依赖性凋亡途径,并激活Tgfbr 1/磷酸肌醇-3- 激酶(PI3K)依赖性存活途径。如果得到证实,我们的研究将提供一种分子机制, 解释CD2AP的缺失如何增强足细胞凋亡和耗竭,从而促进肾小球疾病 基于CD2AP作为TbRI中多途径调节剂的新的基本功能作用, 诱导的信号转导。最近的意见进一步强调了这项工作的重要性 这表明在没有直接遗传缺陷的情况下,CD2AP表达的功能性下调是一个重要的因素。 在小鼠模型和人类肾小球疾病中常见。 具体目标:1。鉴定分子决定簇并表征TGF-β诱导的细胞凋亡的调节。 CD2AP和细胞质Tgfbrl的相互作用。我们将a)确定序列基序和结构模型 和B)将其与Smad结合模型进行比较 由Tgfbrl的GS区和L45环介导。2.研究CD2AP如何介导负调节 Tgfbr1/Smad3信号通路。我们将检查a)CD2AP是否与SmadS竞争结合至 活化的Tgfbr1;和B)CD2 AP靶向内化的Tgfbr1复合物,用于降解和终止 信号3.明确足细胞特异性TGF-β受体信号在足细胞凋亡中的作用, 在体内的消耗,并确定是否足细胞特异性机制的进展, CD2AP-/-小鼠肾小球损伤至肾小球硬化?我们将在体内确定a)条件性的 使用cre/lox技术缺失足细胞中的TGF-β受体II型(Tgfbr 2)可防止足细胞 CD2 AP-/-小鼠中的细胞凋亡、耗竭和/或肾小球硬化;和B)是否足细胞特异性, TGF-β受体信号转导的受控激活足以诱导足细胞凋亡,足细胞凋亡是一种重要的细胞因子。 使用强力霉素诱导的组成型活性表达的体内消耗和肾小球硬化 Tgfbrl(Tgfbrl(AAD))。
英文摘要
Podocyte depletion is a hallmark of progressive glomerulosclerosis and diabetic nephropathy. CD2- associated protein (CD2AP) is a widely-expressed cytoplasmic adaptor protein that has previously been implicated in podocyte slit diaphragm protein complex formation. CD2AP null mice develop progressive glomerulosclerosis early in life and CD2AP haploinsufficiency is associated with glomerular disease susceptibility in humans. However, it remains unclear how loss of CD2AP function may cause glomerulosclerosis. In this renewal application, we will extend our work to test the hypothesis that CD2AP promotes renal epithelial cell survival by functioning as a molecular switch that suppresses the TGF-beta receptor type I (Tgfbr1)/Smad3-dependent apoptosis pathway and activates a Tgfbrl/phosphoinositide-3- kinase (PI3K) -dependent survival pathway. If confirmed, our studies will provide a molecular mechanism to explain how loss of CD2AP may enhance podocyte apoptosis and depletion to promote glomerular disease in mice and men based on a novel, essential functional role for CD2AP as multi-pathway regulator in TbRI- induced signal transduction. The relevance of this work is further underscored by recent observations suggesting that in the absence of direct genetic defects, functional downregulation of CD2AP expression is a common finding in mouse models and human glomerular disease. Specific Aims: 1. Identify the molecular determinants and characterize the regulation of the TGF-p-inducible interaction of CD2AP and cytoplasmic Tgfbrl. We will a) determine the sequence motif and structural model of Tgfbrl that underlies the interaction with CD2AP, and b) compare it with the Smad-binding model mediated by the GS region and L45 loop of Tgfbrl. 2. Investigate how CD2AP mediates negative regulation of Tgfbr1/Smad3 signaling. We will examine whether a) CD2AP competes with SmadS for binding to activated Tgfbrl; and b) CD2AP targets internalized Tgfbrl complexes for degradation and termination of signaling. 3. Define the role of podocyte-specific TGF-b receptor signaling in podocyte apoptosis and depletion in vivo, and determine whether this podocyte-specific mechanism underlies the progression of glomerular injury to glomerulosclerosis in CD2AP-/- mice? We will determine in vivo whether a) conditional deletion of TGF-b receptor type II (Tgfbr2) in podocytes using cre/lox technology prevents podocyte apoptosis, depletion, and/or glomerulosclerosis in CD2AP-/- mice; and b) whether podocyte-specific, controlled activation of TGF-(3 receptor signaling is sufficient to induce podocyte apoptosis, podocyte depletion and glomerulosclerosis in vivo using doxycycline-inducible expression of constitutively active Tgfbrl (Tgfbrl (AAD)).
期刊论文(6)
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科研奖励(0)
会议论文
DOI: 10.1161/circresaha.113.301921
发表时间: 2013-09-27
期刊: Circulation research
影响因子: 20.1
作者: [Xie WB, Li Z, Shi N, Guo X, Tang J, Ju W, Han J, Liu T, Bottinger EP, Chai Y, Jose PA, Chen SY]
通讯作者: Chen SY
DOI: 10.1152/ajprenal.00559.2007
发表时间: 2008-10
期刊: American journal of physiology. Renal physiology
影响因子: --
作者: [Saleem MA, Zavadil J, Bailly M, McGee K, Witherden IR, Pavenstadt H, Hsu H, Sanday J, Satchell SC, Lennon R, Ni L, Bottinger EP, Mundel P, Mathieson PW]
通讯作者: Mathieson PW
Genomic Medicine Pilot For Hypertension And Kidney Disease In Primary Care
Genomic Medicine Pilot For Hypertension And Kidney Disease In Primary Care
Genomic Medicine Pilot For Hypertension And Kidney Disease In Primary Care
Glomerular Cell-Cell Crosstalk and Injury
国内基金
海外基金
Epac1/2通过蛋白酶体调控中性粒细胞NETosis和Apoptosis在急性肺损伤中的作用研究
  • 批准号:
    LBY21H010001
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2020
  • 负责人:
    郑绪阳
  • 依托单位:
基于Apoptosis/Ferroptosis双重激活效应的天然产物AlbiziabiosideA的抗肿瘤作用机制研究及其结构改造
  • 批准号:
    81703335
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    20.0万元
  • 批准年份:
    2017
  • 负责人:
    卫高菲
  • 依托单位:
双肝移植后Apoptosis和pyroptosis在移植物萎缩差异中的作用和供受者免疫微环境变化研究
  • 批准号:
    81670594
  • 项目类别:
    面上项目
  • 资助金额:
    58.0万元
  • 批准年份:
    2016
  • 负责人:
    陈昊
  • 依托单位:
Serp-2 调控apoptosis和pyroptosis 对肝脏缺血再灌注损伤的保护作用研究
  • 批准号:
    81470791
  • 项目类别:
    面上项目
  • 资助金额:
    73.0万元
  • 批准年份:
    2014
  • 负责人:
    董家鸿
  • 依托单位: