Novel Regulatory Mechanisms Underlying Inside-out Integrin Activation

由内而外整合素激活的新调控机制

基本信息

  • 批准号:
    9141784
  • 负责人:
  • 金额:
    $ 44.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-01 至 2021-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Integrins play important roles in basic cellular functions such as adhesion, growth, and migration as well as specialized functions in platelet plug formation during hemostasis and in T cell mediated immune responses. Abnormal expression and hyperactivity of integrins leads to cardiovascular diseases, impaired inflammatory responses, T cell malfunction, and enhanced tumor metastasis. Current integrin inhibitors that block extracellular ligand binding often cause serious adverse effects. Our overall goal is to elucidate the molecular mechanisms that activate integrins more specifically through the inside-out signaling pathway, thus facilitating the development of new therapies targeting this pathway. The main focus of this proposed study is to understand the structural basis of intermolecular interactions and intramolecular rearrangements that modulate integrin activity, thus altering cell adhesion and motility. The inside-out integrin signaling pathway has recently emerged as a new target for suppressing integrin activity. Integrin activation through this pathway is triggered by talin and mediated by a small GTPase, Rap1, and its effector protein RIAM (Rap1-interacting adaptor molecule). A co-activator, kindlin, also significantly enhanced the integrin activity. However, many key questions regarding how specific inter- and intra-molecular interactions regulate inside-out integrin activation remain unanswered. We have previously determined the structural basis of RIAM recruitment by Rap1 and the PM translocation and conformational activation of talin by RIAM. In this proposal, we aim to address the following central questions regarding the conformational rearrangement and specific interactions underlying the functional regulation of RIAM, talin, and kindlin: 1) to elucidate the structural basis of regulatory intramolecular interactions of RIAM and talin; 2) to determine the molecular basis of enhanced talin activity induced by the interaction of RIAM and talin; and 3) to probe the molecular mechanisms underlying the different integrin- regulating properties among kindlin isoforms and the co-localization of kindlin and talin in integrin signaling. Our studies will significantly advance the understanding of the regulatory mechanisms of integrin activation through the inside-out pathway.
项目概要/摘要 整合素在粘附、生长和迁移等基本细胞功能中发挥着重要作用 作为止血过程中血小板栓塞形成和 T 细胞介导的免疫中的特殊功能 回应。整合素的异常表达和过度活跃会导致心血管疾病、受损 炎症反应、T 细胞功能障碍和增强的肿瘤转移。目前的整合素抑制剂 阻断细胞外配体结合常常会造成严重的不良影响。我们的总体目标是阐明 通过由内而外的信号通路更特异性地激活整合素的分子机制,因此 促进针对该途径的新疗法的开发。这项拟议研究的主要重点是 了解分子间相互作用和分子内重排的结构基础 调节整合素活性,从而改变细胞粘附和运动。 由内而外的整合素信号通路最近成为抑制整合素的新靶点 活动。通过该途径的整合素激活由 talin 触发,并由小型 GTP 酶 Rap1 介导, 及其效应蛋白 RIAM(Rap1 相互作用接头分子)。辅助激活剂 kindlin 也显着 增强整合素活性。然而,许多关键问题涉及如何特定的分子间和分子内 相互作用调节由内而外的整合素激活仍然没有答案。 我们之前已经确定了 Rap1 和 PM 招募 RIAM 的结构基础 RIAM 对talin 的易位和构象激活。在本提案中,我们旨在解决以下问题 关于构象重排和特定相互作用的核心问题 RIAM、talin和kindlin的功能调控:1)阐明分子内调控的结构基础 RIAM和talin的相互作用; 2)确定talin活性增强的分子基础 RIAM和talin的相互作用; 3)探索不同整合素背后的分子机制 调节kindlin亚型之间的特性以及kindlin和talin在整合素信号传导中的共定位。 我们的研究将显着促进对整合素激活调节机制的理解 通过由内而外的路径。

项目成果

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Jinhua Wu其他文献

Jinhua Wu的其他文献

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{{ truncateString('Jinhua Wu', 18)}}的其他基金

Molecular Mechanisms Underlying Adaptor-Mediated Integrin Signaling in a Species-Specific Manner
物种特异性方式的接头介导的整合素信号转导的分子机制
  • 批准号:
    10330819
  • 财政年份:
    2016
  • 资助金额:
    $ 44.63万
  • 项目类别:
Molecular Mechanisms Underlying Adaptor-Mediated Integrin Signaling in a Species-Specific Manner
物种特异性方式的接头介导的整合素信号转导的分子机制
  • 批准号:
    10540367
  • 财政年份:
    2016
  • 资助金额:
    $ 44.63万
  • 项目类别:
Molecular Mechanisms Underlying Adaptor-Mediated Integrin Signaling in a Species-Specific Manner
物种特异性方式的接头介导的整合素信号转导的分子机制
  • 批准号:
    10792668
  • 财政年份:
    2016
  • 资助金额:
    $ 44.63万
  • 项目类别:
Molecular Mechanisms Underlying Adaptor-Mediated Integrin Signaling in a Species-Specific Manner
物种特异性方式的接头介导的整合素信号转导的分子机制
  • 批准号:
    10591322
  • 财政年份:
    2016
  • 资助金额:
    $ 44.63万
  • 项目类别:
Novel selective alpha4beta2 nicotinic receptor antagonists for smoking cessation
用于戒烟的新型选择性α4β2烟碱受体拮抗剂
  • 批准号:
    8779197
  • 财政年份:
    2014
  • 资助金额:
    $ 44.63万
  • 项目类别:
Novel selective alpha4beta2 nicotinic receptor antagonists for smoking cessation
用于戒烟的新型选择性α4β2烟碱受体拮抗剂
  • 批准号:
    9152806
  • 财政年份:
    2014
  • 资助金额:
    $ 44.63万
  • 项目类别:
Novel selective alpha4beta2 nicotinic receptor antagonists for smoking cessation
用于戒烟的新型选择性α4β2烟碱受体拮抗剂
  • 批准号:
    9276893
  • 财政年份:
    2014
  • 资助金额:
    $ 44.63万
  • 项目类别:

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