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.

项目总结