Integration of inflammation and cancer by molecular chaperone

分子伴侣整合炎症和癌症

基本信息

  • 批准号:
    10056559
  • 负责人:
  • 金额:
    $ 16.12万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-01-01 至 2021-12-31
  • 项目状态:
    已结题

项目摘要

Project Summary Chronic and unrelenting inflammation contributes unequivocally to oncogenesis. However, there are many fundamental challenges in the field of onco-inflammation. Among them, systematic study has not been done to quantitatively and qualitatively identify and characterize the type of inflammations that is particularly oncogenic. We hypothesize that oncogenic inflammation is genotoxic and modulated by key innate immune receptors such as Toll-like receptors (TLRs) in a cell type-specific fashion (Hypothesis 1). In addition, despite the extensive study of the cancer genome, fewer studies have addressed the roles of protein quality control in inflammation and oncogenesis. Cancer cells, as compared to normal cells, have a high metabolic demand which increases the need for protein chaperones that accelerate protein folding. We thus propose that there is a cancer-specific HSP-client network that plays pivotal roles in inflammation and cancer (Hypothesis 2). Molecular chaperone gp96 is a paralogue of HSP90 in the endoplasmic reticulum. It is uniformly expressed at a high level in human cancers, and the high expression of gp96 correlates with worse prognosis. Intriguingly, we discovered that gp96 is an obligated master chaperone for TLRs. We further revealed that deletion of gp96 in Mφs protect mice against colitis-associated colon cancer, which correlates with a reduced cytokine level and protection against mutation of Ctnnb1 encoding β-catenin. We have also generated cell type-specific gp96 KO mice by deleting gp96 in B cells, regulatory T cells, gut epithelial cells, platelets and dendritic cells. These unique models allow us to quantify the extent of contribution by these immune cell subsets to inflammation- associated cancer. In addition, we have shown that gp96 plays essential roles in chaperoning several other strategically important clients in oncogenesis, including integrins, Wnt co-receptor, Her2, IGF-1 and surface TGFβ docking receptor LRRC32 (GARP). Our findings suggest that gp96 drives oncogenesis by integrating cell-intrinsic oncogenic client network with inflammation (Hypothesis 3). We will address our hypotheses by first determining if oncogenic inflammation is modulated by the TLR master chaperone gp96 in a cell type-specific fashion, using a battery of unique genetic tools. We will then complete the high resolution mapping of cancer- specific gp96-client network via genetic, pharmacological and biochemical means. The ultimate goal of this US-China joint project (RFA-AI-16-006) is to uncover both cancer-intrinsic and cancer- extrinsic roles of gp96 in oncogenesis to guide the development of novel cancer therapeutics in the future.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Zihai Li其他文献

Zihai Li的其他文献

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{{ truncateString('Zihai Li', 18)}}的其他基金

Sexual Dimorphism in T Cell Exhaustion and Bladder Cancer
T 细胞耗竭和膀胱癌中的性别二态性
  • 批准号:
    10629078
  • 财政年份:
    2023
  • 资助金额:
    $ 16.12万
  • 项目类别:
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy Supplement
靶向 GRP94-TGF-β 通路的癌症免疫治疗补充剂
  • 批准号:
    10818173
  • 财政年份:
    2021
  • 资助金额:
    $ 16.12万
  • 项目类别:
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy
靶向 GRP94-TGF-β 通路的癌症免疫治疗
  • 批准号:
    10474548
  • 财政年份:
    2021
  • 资助金额:
    $ 16.12万
  • 项目类别:
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy
靶向 GRP94-TGF-β 通路的癌症免疫治疗
  • 批准号:
    10689068
  • 财政年份:
    2021
  • 资助金额:
    $ 16.12万
  • 项目类别:
Targeting GRP94-TGF-beta Pathway for Cancer Immunotherapy
靶向 GRP94-TGF-β 通路的癌症免疫治疗
  • 批准号:
    10275810
  • 财政年份:
    2021
  • 资助金额:
    $ 16.12万
  • 项目类别:
Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
癌症生物学和治疗中的内质网伴侣
  • 批准号:
    9321008
  • 财政年份:
    2015
  • 资助金额:
    $ 16.12万
  • 项目类别:
Project 1: Definition of grp94-GARP-TGFbeta Axis in Cancer Biology and Clinical Significance
项目1:grp94-GARP-TGFbeta轴在癌症生物学中的定义及其临床意义
  • 批准号:
    8934513
  • 财政年份:
    2015
  • 资助金额:
    $ 16.12万
  • 项目类别:
Novel mechanisms of UPR sensing and nonalcoholic fatty liver disease
UPR传感和非酒精性脂肪肝的新机制
  • 批准号:
    9026108
  • 财政年份:
    2015
  • 资助金额:
    $ 16.12万
  • 项目类别:
Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
癌症生物学和治疗中的内质网伴侣
  • 批准号:
    8934510
  • 财政年份:
    2015
  • 资助金额:
    $ 16.12万
  • 项目类别:
Endoplasmic Reticulum Chaperones in Cancer Biology and Therapy
癌症生物学和治疗中的内质网伴侣
  • 批准号:
    9770790
  • 财政年份:
    2015
  • 资助金额:
    $ 16.12万
  • 项目类别:

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