Pathologic Mechanisms of Polycystic Kidney Disease

多囊肾的病理机制

基本信息

  • 批准号:
    7941657
  • 负责人:
  • 金额:
    $ 8.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-30 至 2012-09-29
  • 项目状态:
    已结题

项目摘要

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is caused by mutations in the genes encoding polycystin-1 and/or polycystin-2, but results in epithelial cells with disrupted adherensjunctions and compromised beta-catenin signaling pathways. Our data showthe polycystins in a multiprotein complex with adherens junction components. The complexes are associated with plasma membranemicrodomains containing the structural lipid raft protein flotillin-2, but not similar microdomains containing caveolin. Disruption of the adherens junction complexes is linked to down regulation of LAR family receptortyrosine phosphatases and hyperphosphorylation of the proteins in the complex. Since adherens junctions provide structural stability to the epithelial sheet through connections to the actin cytoskeleton, and such connections are compromised in ADPKD, these alterations are likely to contribute to the disease pathology. We hypothesize that flotillin-2 membrane microdomains represent sites wherethe polycystins are activated and cooperate with signaling molecules to bring about stable cell-cell adhesion. Consequently,when polycystin-1 function is mutant or absent, the signaling to initiate cell adhesionis altered and changes in renalcystogenic potential result. The experiments in this proposalwill elucidate the organization and function of the polycystin-containing multiprotein complexes associated with the flotillin-2 membranemicrodomainsby probing for colocalized tyrosine kinases and phosphatases and by monitoringthe contribution of flotillin-2 rafts to actin remodeling, membranetrafficking and stable cell-cell adhesion. Successfulcompletion of the proposed experiments will provide new, mechanistic information on the temporal sequence of eventsleading from polycystin-1activation to the stabilization of E-cadherin mediated adhesion. These mechanistic insights are expected to be useful for designing therapeutic interventions, particularly those that make use of kinase inhibitors.
常染色体显性多囊肾病(ADPKD)是由基因编码突变引起的

项目成果

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Angela Wandinger-Ness其他文献

Angela Wandinger-Ness的其他文献

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{{ truncateString('Angela Wandinger-Ness', 18)}}的其他基金

Ketorolac and Related NSAIDs for Targeting Rho-family GTPases in Ovarian Cancer
酮咯酸和相关 NSAID 靶向治疗卵巢癌中的 Rho 家族 GTP 酶
  • 批准号:
    9205393
  • 财政年份:
    2016
  • 资助金额:
    $ 8.99万
  • 项目类别:
Fluorescence Microscopy and Cell Imaging Shared Resource
荧光显微镜和细胞成像共享资源
  • 批准号:
    8180650
  • 财政年份:
    2010
  • 资助金额:
    $ 8.99万
  • 项目类别:
Academic Science Education and Research Training
学术科学教育和研究培训
  • 批准号:
    8549630
  • 财政年份:
    2009
  • 资助金额:
    $ 8.99万
  • 项目类别:
Academic Science Education and Research Training
学术科学教育和研究培训
  • 批准号:
    8327102
  • 财政年份:
    2009
  • 资助金额:
    $ 8.99万
  • 项目类别:
Academic Science Education and Research Training
学术科学教育和研究培训
  • 批准号:
    8538444
  • 财政年份:
    2009
  • 资助金额:
    $ 8.99万
  • 项目类别:
Research Project 3: Dissecting the spatio-temporal coordination of endocytic traf
研究项目3:剖析内吞运输的时空协调
  • 批准号:
    8919390
  • 财政年份:
    2009
  • 资助金额:
    $ 8.99万
  • 项目类别:
Academic Science Education and Research Training
学术科学教育和研究培训
  • 批准号:
    7691522
  • 财政年份:
    2009
  • 资助金额:
    $ 8.99万
  • 项目类别:
Academic Science Education and Research Training
学术科学教育和研究培训
  • 批准号:
    10248411
  • 财政年份:
    2009
  • 资助金额:
    $ 8.99万
  • 项目类别:
Academic Science Education and Research Training
学术科学教育和研究培训
  • 批准号:
    8144802
  • 财政年份:
    2009
  • 资助金额:
    $ 8.99万
  • 项目类别:
Academic Science Education and Research Training
学术科学教育和研究培训
  • 批准号:
    9548263
  • 财政年份:
    2009
  • 资助金额:
    $ 8.99万
  • 项目类别:

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通过破坏粘附连接相关的 RNAi 机制,口腔病原体介导促肿瘤转化
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粘着斑和粘附连接在骨力传感和力转导中的功能和相互作用。
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    17K17307
  • 财政年份:
    2017
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    Grant-in-Aid for Young Scientists (B)
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α-连环蛋白及其在粘附连接组装和功能中的结合伙伴
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