Mechanistic difference of NF-kappaB in lung physiology and tumorigenesis

NF-κB在肺生理和肿瘤发生中的机制差异

基本信息

  • 批准号:
    10443227
  • 负责人:
  • 金额:
    $ 38.98万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-24 至 2027-07-31
  • 项目状态:
    未结题

项目摘要

Abstract The transcription factor NF-κB is critically important for tumorigenesis and therapeutic resistance but we have been unable to successfully target it for clinical treatment due to its equally important roles in physiology and host defense in particular. Teasing apart these functions of NF-κB will overcome this barrier resulting in a powerful means to fight cancer. While the core mechanism driving NF-κB activation has been well defined and is the same under most physiological and oncogenic conditions, the mechanistic difference in physiological vs. oncogenic NF-κB still remains a conundrum. Recently, we have demonstrated, for the first time, that extrinsic/ inflammatory and intrinsic/oncogenic signals induce different activation patterns and different forms of NF-κB in normal lung cells and lung cancer cells. Moreover, we have identified, also for the first time, the PDZ-LIM domain-containing protein PDLIM2 that selectively suppresses the ‘oncogenic’ but not ‘physiologic’ activation of NF-κB and can be targeted as mono- or combination therapy in murine models of lung cancer. Based on these novel discoveries, in this proposal we will determine the molecular mechanisms by which PDLIM2 acts as a determinant of NF-κB function. We will also dissect the roles and molecular mechanisms of this regulation of the ‘oncogenic’ and ‘physiologic’ activation of NF-κB in lung tumorigenesis and physiological host defense against pulmonary infection. These studies are significant, because we know NF-κB is a strong tumor promoter linked to almost all human cancers but cannot currently be targeted in the clinic given its physiological importance. Also, these studies have both conceptual and technical innovations regarding NF-κB and cancer, since they open new avenues to study the differential regulation and action of NF-κB in cancer and physiology, and may lead to new clinically feasible approaches to selectively target pathogenic NF-κB for cancer therapy.
摘要

项目成果

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Zhaoxia Qu其他文献

Zhaoxia Qu的其他文献

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{{ truncateString('Zhaoxia Qu', 18)}}的其他基金

Structural and molecular dissection of NF-kappaB regulation by the ubiquitin E3 ligase PDLIM2 in lung innate immunity and diseases
肺先天免疫和疾病中泛素 E3 连接酶 PDLIM2 调节 NF-kappaB 的结构和分子解析
  • 批准号:
    10586099
  • 财政年份:
    2022
  • 资助金额:
    $ 38.98万
  • 项目类别:
Administrative Supplement: Dissection of NF-kappaB regulation by the ubiquitin E3 ligase PDLIM2 in lung innate immunity and diseases
行政补充:泛素 E3 连接酶 PDLIM2 在肺先天免疫和疾病中对 NF-kappaB 调节的剖析
  • 批准号:
    10784300
  • 财政年份:
    2022
  • 资助金额:
    $ 38.98万
  • 项目类别:
Mechanistic difference of NF-kappaB in lung physiology and tumorigenesis
NF-κB在肺生理和肿瘤发生中的机制差异
  • 批准号:
    10689678
  • 财政年份:
    2022
  • 资助金额:
    $ 38.98万
  • 项目类别:
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