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Cytoskeletal Linking Proteins in Liver Function

Cytoskeletal Linking Proteins in Liver Function
肝功能中的细胞骨架连接蛋白
批准号:
6883269
负责人:
R. BRIAN DOCTOR
金额:
$25.41万
依托单位国家:
美国
项目类别:
财政年份:
2002
资助国家:
美国
项目状态:
已结题
起止时间:
2002-06-15 至 2007-03-31

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中文摘要
翻译
描述(由申请方提供):肝脏形成胆汁的结果 来自肝细胞的胆汁盐和有机溶质的顶端分泌, 氯化物、碳酸氢盐和水。这种载体分泌物 需要严格的两极分化和协调调节不同的 两种细胞中的转运蛋白。基本营养素的分布和活性 肝细胞中的转运蛋白(例如多药耐药蛋白2; mrp 2)和胆管细胞(例如囊性纤维化跨膜传导 调节因子(CFTR)通过cAMP调节。活动或分布减少 许多胆汁淤积性肝病的假定基础。 在其他细胞类型中,表达PDZ结构域的蛋白质将膜蛋白拴系到 细胞骨架和调节其分布,保留,聚类和 膜微区内的活性。在上皮细胞中, Ezrin-Radixin-Moesin结合磷蛋白50(EBP 50)已经涉及到 调节cAMP依赖性顶端转运事件。我们最近的研究 实验室证明,EBP 50高度集中在 肝细胞和胆管细胞。EBP 50-CFTR相互作用的破坏 胆管细胞导致CFTR的cAMP活化丧失, CFTR依赖性细胞体积调节。EBP 50放大这些的机制 对CFTR的影响在研究中显示,EBP 50能够 在体外和体内均寡聚化。假设EBP 50服务于 在胆汁形成的能力和调节中起关键作用, 研究将(1)描述以下因素的调节和功能影响: EBP 50寡聚化;(2)描述EBP 50在 调节胆管细胞中CFTR的分布和活性;和(3)比较 并将EBP 50-CFTR功能范例发育的胆管细胞与对照组进行对比。 肝细胞中EBP 50-mrp 2相互作用的功能后果。这条线 调查的巨大希望,提供新的见解, 调节胆汁形成和胆汁淤积性肝病的潜在机制。
英文摘要
DESCRIPTION (provided by applicant): The formation of bile by the liver results from apical secretion of bile salts and organic solutes from hepatocytes and chloride, bicarbonate and water from cholagniocytes. This vectorial secretion requires the strict polarization and coordinated regulation of distinct transporters in both cell types. The distribution and activity of essential transporter proteins in hepatocytes (e.g. multi-drug resistance protein 2; mrp2) and cholangiocytes (e.g. cystic fibrosis transmembrane conductance regulator; CFTR) is regulated through cAMP. Decreased activity or distribution of transporters represents a putative basis of many cholestatic liver diseases. In other cell types, PDZ domain-expressing proteins tether membrane proteins to the cytoskeleton and moderate their distribution, retention, clustering and activity within membrane microdomains. In epithelial cells, Ezrin-Radixin-Moesin binding phosphoprotein 50 (EBP50) has been implicated in modulating cAMP-dependent apical transport events. Recent studies in our laboratory demonstrate EBP50 is highly concentrated at the apical domain of hepatocytes and cholangiocytes. Disruption of the EBP50-CFTR interaction in cholangiocytes results in the loss of cAMP activation of CFTR and CFTR-dependent cell volume regulation. A mechanism for EBP50 to amplify these effects on CFTR were revealed in studies that showed EBP50 is capable of oligomerizing both in vitro and in vivo. Hypothesizing that EBP50 serves a pivotal role in the capacity and regulation of bile formation, the proposed studies will (1) characterize the regulation and functional implications of EBP50 oligomerization; (2) delineate the physiologic role of EBP50 in modulating CFTR distribution and activity in cholangiocytes; and (3) compare and contrast the EBP50-CFTR functional paradigm developed cholangiocytes to the functional consequences of the EBP50-mrp2 interaction in hepatocytes. This line of investigation holds great promise in providing novel insights into the mechanisms underlying regulated bile formation and cholestatic liver disease.
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Cytoskeletal linking proteins in renal epithelial cell function
  • 批准号:
    7780154
  • 项目类别:
  • 资助金额:
    $36.42万
  • 财政年份:
    2009
  • 负责人:
    R. BRIAN DOCTOR
  • 依托单位:
Cytoskeletal linking proteins in renal epithelial cell function
  • 批准号:
    8305643
  • 项目类别:
  • 资助金额:
    $32.25万
  • 财政年份:
    2009
  • 负责人:
    R. BRIAN DOCTOR
  • 依托单位:
Cytoskeletal linking proteins in renal epithelial cell function
  • 批准号:
    8131593
  • 项目类别:
  • 资助金额:
    $38.37万
  • 财政年份:
    2009
  • 负责人:
    R. BRIAN DOCTOR
  • 依托单位:
Cytoskeletal linking proteins in renal epithelial cell function
  • 批准号:
    8133229
  • 项目类别:
  • 资助金额:
    $6.18万
  • 财政年份:
    2009
  • 负责人:
    R. BRIAN DOCTOR
  • 依托单位:
海外基金