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.

项目概要 慢性且持续的炎症无疑会导致肿瘤发生。然而，有很多 肿瘤炎症领域的根本挑战。其中，尚未进行系统研究 定量和定性地识别和表征特别致癌的炎症类型。 我们假设致癌炎症具有基因毒性并受到关键先天免疫受体的调节 例如细胞类型特异性的 Toll 样受体 (TLR)（假设 1）。此外，尽管 对癌症基因组的广泛研究，很少有研究探讨蛋白质质量控​​制在癌症中的作用 炎症和肿瘤发生。与正常细胞相比，癌细胞具有较高的代谢需求 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 癌症特异性 HSP 客户网络在炎症和癌症中发挥关键作用（假设 2）。 分子伴侣 gp96 是内质网中 HSP90 的旁系同源物。统一表示为 gp96 在人类癌症中水平较高，并且 gp96 的高表达与较差的预后相关。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 Mφs 可以保护小鼠免受结肠炎相关结肠癌的侵害，这与细胞因子水平降低和 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 通过删除 B 细胞、调节性 T 细胞、肠上皮细胞、血小板和树突状细胞中的 gp96 来对小鼠进行实验。这些 独特的模型使我们能够量化这些免疫细胞亚群对炎症的贡献程度—— 相关癌症。此外，我们还表明 gp96 在陪伴其他几种药物方面发挥着重要作用。 在肿瘤发生过程中具有重要战略意义的客户，包括整合素、Wnt 共受体、Her2、IGF-1 和表面蛋白 TGFβ 对接受体 LRRC32 (GARP)。我们的研究结果表明 gp96 通过整合来驱动肿瘤发生 细胞内在致癌客户网络与炎症（假设 3）。我们将首先解决我们的假设 确定细胞类型特异性中的致癌炎症是否由 TLR 主伴侣 gp96 调节 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绘图—— 通过遗传、药理学和生化手段特定的 gp96-客户网络。 这个中美联合项目 (RFA-AI-16-006) 的最终目标是揭示癌症本质和癌症- gp96 在肿瘤发生中的外在作用，以指导未来新型癌症疗法的开发。