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中文摘要
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描述(由申请方提供):I型干扰素(IFN-?/?)的抗肿瘤疗效治疗是可变的,因为它可以诱导肿瘤细胞生长抑制或凋亡。I型IFN诱导的细胞凋亡的潜在分子机制在很大程度上仍然未知。确定由I型IFN激活的导致肿瘤细胞破坏的信号通路具有临床重要性。我们的初步数据表明,STAT 2的缺陷会阻止细胞接受IFN-γ。诱导的细胞凋亡,这种缺陷与干扰素刺激基因(ISG)表达受损相关。我们已经发现,促凋亡蛋白Bim,破坏线粒体的完整性,被激活的I型干扰素在STAT 2依赖的方式。重要的是,Bim和STAT 2信号之间可能存在串扰,因为在Bim或STAT 2缺陷的小鼠胚胎成纤维细胞中I型IFN的凋亡活性受损。 基于我们的数据,我们的假设是I型IFN诱导的STAT 2活性通过调节仅BH 3结构域的Bcl-2蛋白的促凋亡活性来调节线粒体依赖性死亡途径的活化。 具体目的:1)确定STAT 2调节Bim激活的机制。2)表征STAT 2中的保守残基并确定它们是否调节I型IFN信号传导和Bim活化。3)确定STAT 2是如何在体内I型干扰素的抗肿瘤作用所需的。 重要性:这些结果将提供深入了解I型IFN诱导的细胞凋亡的信号转导机制和抗肿瘤疗效的STAT 2和Bim的调节。 公共卫生相关性:干扰素是一个可溶性蛋白家族,已知其在抗病毒宿主防御和细胞生长抑制中的功能。STAT 2是介导IFN抗病毒作用所需的关键分子,但对其在癌症中的功能作用知之甚少。我们的项目将解决干扰素限制肿瘤生长的分子机制。
英文摘要
DESCRIPTION (provided by applicant): The antitumor efficacy of type I interferon (IFN-?/?) therapy is variable since it can induce either tumor cell growth inhibition or apoptosis. The underlying molecular mechanisms of type I IFN-induced apoptosis remain largely unknown. Defining the signaling pathways activated by type I IFNs leading to tumor cell destruction are of clinical importance. Our preliminary data indicates that a deficiency in STAT2 prevents cells from undergoing IFN-?-induced apoptosis and this defect correlates with impaired expression of interferon stimulated genes (ISGs). We have found that the pro-apoptotic protein Bim, which disrupts mitochondrial integrity, is activated by type I IFNs in a STAT2-dependent manner. Importantly, crosstalk between Bim and STAT2 signals likely exists since the apoptotic activity of type I IFNs is impaired in mouse embryonic fibroblasts deficient in either Bim or STAT2. Based on our data, our hypothesis is that type I IFN-induced STAT2 activity regulates the activation of the mitochondrial dependent death pathway by modulating the pro-apoptotic activities of BH3 domain only Bcl-2 proteins. Specific Aims: 1) Determine the mechanism by which STAT2 modulates Bim activation. 2) Characterize conserved residues in STAT2 and determine whether they modulate type I IFN signaling and Bim activation. 3) Determine how STAT2 is required for the in vivo antitumor effects of type I IFNs. Significance: These results will provide insights into the signaling mechanisms and antitumor efficacy of type I IFN-induced apoptosis that are regulated by STAT2 and Bim. PUBLIC HEALTH RELEVANCE: Interferons are a family of soluble proteins that are known for their function in antiviral host defense and cell growth inhibition. STAT2 is a critical molecule required for mediating the antiviral effects of IFN but little is known about its functional role in cancer. Our project will address a molecular mechanism by which interferons restrict tumor growth.
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Investigation of STAT2 Signaling in the tumor microenvironment
  • 批准号:
    10661993
  • 项目类别:
  • 资助金额:
    $7.93万
  • 财政年份:
    2023
  • 负责人:
    ANA M GAMERO
  • 依托单位:
STAT2 Signaling in the Pathogenesis of Psoriasis
  • 批准号:
    10418798
  • 项目类别:
  • 资助金额:
    $17.26万
  • 财政年份:
    2021
  • 负责人:
    ANA M GAMERO
  • 依托单位:
STAT2 Signaling in the Pathogenesis of Psoriasis
  • 批准号:
    10303865
  • 项目类别:
  • 资助金额:
    $20.92万
  • 财政年份:
    2021
  • 负责人:
    ANA M GAMERO
  • 依托单位:
The Role of STAT2 in Flat Non-Polypoid Colorectal Neoplasia
  • 批准号:
    9305364
  • 项目类别:
  • 资助金额:
    $7.8万
  • 财政年份:
    2017
  • 负责人:
    ANA M GAMERO
  • 依托单位:
海外基金