Integration of inflammation and cancer by molecular chaperone

分子伴侣整合炎症和癌症

• 批准号: 10056559
• 负责人: Zihai Li
• 金额: $ 16.12万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10056559
• 关键词: Academy; Address; Animal Experiments; B-Lymphocytes; Biochemical; Blood Platelets; Breast; Cells; Cellular biology; China; Chinese People; Chronic; Chronic Disease; Client; Colitis; Collaborations; Colon Carcinoma; Defense Mechanisms; Dendritic Cells; Development; Diagnostic; Docking; Endoplasmic Reticulum; Epithelial Cells; Equilibrium; Estrogen Receptor alpha; Failure; Future; Genetic; Goals; Heat shock proteins; Heat-Shock Proteins 90; Homeostasis; Human; IGF1 gene; Immune; Immune response; Immune system; Immunologic Receptors; Immunologic Surveillance; Inflammation; Institutes; Insulin-Like Growth Factor I; Integrins; Joints; Knockout Mice; LRRC32 gene; Laboratories; Lead; Link; Literature; Liver; Lung; Malignant Neoplasms; Medical; Metabolic; Microbiology; Modeling; Molecular Chaperones; Multiple Myeloma; Mus; Mutation; Neurodegenerative Disorders; Non-Steroidal Anti-Inflammatory Agents; Normal Cell; Obesity; Oncogenic; Oral; Organ; Pharmacology; Phase; Plant Roots; Play; Process; Protein Chemistry; Proteins; Quality Control; Reagent; Regulatory T-Lymphocyte; Research; Resolution; Role; Science; South Carolina; Stomach; Surface; Therapeutic; Tissues; Toll-like receptors; Transforming Growth Factor beta; Universities; Urokinase Plasminogen Activator Receptor; beta catenin; cancer cell; cancer genome; cancer prevention; cancer risk; cell transformation; cell type; cytokine; gastrointestinal epithelium; genotoxicity; interest; new therapeutic target; novel; outcome forecast; prognostic tool; programs; protein folding; receptor; response to injury; theories; tool; tumorigenesis

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.

项目摘要 慢性炎症和不屈不挠的炎症明确促进了肿瘤发生。但是，有很多 Onco炎症领域面临的基本挑战。其中，系统的研究尚未进行 定量和定性地识别和表征特别致癌的炎症类型。 我们假设致癌性炎症是遗传毒性的，并由关键的先天免疫接收器调节 例如以特异性细胞类型的方式（假设1），例如Toll样受体（TLR）。此外，dospite 对癌症基因组的广泛研究，更少的研究解决了蛋白质质量控​​制在 炎症和肿瘤发生。与正常细胞相比，癌细胞的代谢需求很高 这增加了对加速蛋白质折叠的蛋白质伴侣的需求。因此，我们建议有 在炎症和癌症中扮演关键作用的癌症特异性HSP-client网络（假设2）。 分子伴侣GP96是内质网中HSP90的旁程。它均匀地表达 人类癌症的高水平，GP96的高表达与预后较差有关。有趣的是， 我们发现GP96是TLR的义务主伴侣。我们进一步揭示了gp96的删除 在MφS中，保护小鼠免受结肠炎相关的结肠癌，这与细胞因子水平降低相关 防止编码β-catenin的CTNNB1突变。我们还生成了细胞类型特异性GP96 KO 通过在B细胞，调节性T细胞，肠道上皮细胞，血小板和树突状细胞中删除GP96的小鼠。这些 独特的模型使我们能够量化这些免疫细胞子集对炎症的贡献程度 - 相关癌症。此外，我们已经证明GP96在伴侣中扮演着重要的作用 在肿瘤发生方面具有战略意义的客户，包括整联蛋白，Wnt共受体，HER2，IGF-1和Surface TGFβ对接受体LRC32（GARP）。我们的发现表明，GP96通过整合驱动造成肿瘤 具有炎症的细胞中性致癌客户网络（假设3）。我们将首先解决我们的假设 确定在细胞类型特异性中TLR主伴侣GP96调节致癌性炎症是否是调节的 时尚，使用一系列独特的遗传工具。然后，我们将完成癌症的高分辨率映射 - 通过遗传，药物和生化手段的特定GP96-CLIENT网络。 这个美国 - 中国联合项目（RFA-AI-16-006）的最终目标是发现癌症和癌症 - GP96在肿瘤发生中的外在作用指导未来新型癌症治疗的发展。