Defining the role of CNPY2 in promoting tumor progression through mediation of macrophage.

定义 CNPY2 通过巨噬细胞介导促进肿瘤进展的作用。

• 批准号: 10657859
• 负责人: Feng Hong
• 金额: $ 46.37万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-13 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657859
• 关键词: Ablation; Address; Attenuated; Biochemical; Biochemistry; Biometry; Cancer Biology; Carcinogens; Cell Death Induction; Cells; Cellular Stress; Cessation of life; Chemicals; Chronic; Cytoprotection; Data; Data Set; Development; Diagnosis; Diethylnitrosamine; Endoplasmic Reticulum; Ensure; Environment; Epidemic; Exposure to; FLT1 gene; Foundations; Functional disorder; Genetic; Genetic Transcription; Goals; Hepatic; Hepatotoxicity; Homologous Gene; Hypoxia; IL6 gene; ITGAM gene; Immune; Immunology; Immunosuppression; Immunotherapy; Infectious Agent; Infiltration; Inflammation; Inflammatory; Invaded; KDR gene; Knock-out; Knockout Mice; Kupffer Cells; Ligands; Liver; Macrophage; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Mediation; Modeling; Mus; Myeloid Cells; Nutrient; Oncology; Pathology; Pathway interactions; Persons; Play; Primary carcinoma of the liver cells; Production; Proliferating; Proteins; Public Health; Quality Control; Receptor Signaling; Regulation; Research; Research Personnel; Role; Signal Transduction; Structure; System; TLR4 gene; TNF gene; Therapeutic; Toll-like receptors; Transactivation; Tumor Immunity; Tumor Promotion; Tumor-associated macrophages; United States; Wild Type Mouse; Work; cancer cell; cancer type; cell motility; coping; cytokine; design; drug development; endoplasmic reticulum stress; genetic approach; improved; inhibitor; liver function; migration; mouse model; new therapeutic target; novel; prevent; proteostasis; rational design; response; structural biology; success; synergism; transcription factor CHOP; transcriptome sequencing; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis

Abstract Liver cancer is one of the most common types of cancer. More than 700,000 people are diagnosed with this cancer each year throughout the world. Liver cancer is responsible for more than 30,000 new cases and 12,000 deaths a year in the United States. Liver cancer has been found to be highly associated with ER stress/unfolded protein response (UPR)-induced chronic inflammation; however, the mechanisms remain unclear. Using a genetic approach, we have found that deletion of an ER protein, CNPY2, from macrophages prevents carcinogen-induced hepatocellular carcinoma, accompanied by reduced ER stress/UPR signals and tumor- associated macrophages in tumors. Furthermore, CNPY2 is required for pro-inflammatory cytokines, IL6 and TNFα released from Kupffer cells/liver macrophages. We also observed that CNPY2 plays a central role in regulating both ER stress/UPR and TLR4 signaling, two pathways known to promote cytokine production and differentiation of macrophages. Together these observations suggested that CNPY2 promotes liver oncogenesis through regulation of macrophages. In this proposal, I will aim to address several fundamental questions in the field of HCC: 1) what is the mechanism by which CNPY2 transcriptionally regulates production of IL6 and IL23 in macrophages. Are both the UPR and TLR4 pathways involved in this regulation? 2) what is the biochemical and structural basis for the roles of CNPY2 in promoting TLR4 signaling-dependent cytokine production in macrophages. Solving crystal structure of CNPY2 will help drug development against CNPY2. 3) The potential mechanism by which CNPY2 regulates differentiation, infiltration and function of tumor-associated macrophages in HCC. 4) What is the role of CNPY2 in tumor immunity? Does targeting CNPY2 improve anti-tumor immunity in HCC? Our traditional and conditional Cnpy2 KO mice are unique models for addressing these questions. Successful execution of this work will significantly advance the field. In the longer term, this study may lay a strong foundation for the development of a new class of therapeutics for cancer, based on the rational design of CNPY2 inhibitors against tumor-associated macrophages.

抽象的 肝癌是最常见的癌症之一。超过70万人被诊断出 每年全世界的癌症。肝癌负责30,000多个新病例和12,000例 美国一年死亡。发现肝癌与ER应力/展开高度相关 蛋白质反应（UPR）诱导的慢性炎症；但是，这些机制尚不清楚。 使用遗传方法，我们发现巨噬细胞中ER蛋白CNPY2的缺失可防止 致癌物诱导的肝细胞癌，通过减少ER应力/UPR信号和肿瘤来完成 肿瘤中的相关巨噬细胞。此外，促炎细胞因子，IL6和 TNFα从kupffer细胞/肝巨噬细胞释放。我们还观察到CNPY2在 调节ER应力/UPR和TLR4信号传导，这是已知促进细胞因子产生和的两种途径 巨噬细胞的分化。这些观察结果共同表明CNPY2促进了肝脏肿瘤发生 通过调节巨噬细胞。 在此提案中，我将旨在解决HCC领域的几个基本问​​题：1） CNPY2转录调节巨噬细胞中IL6和IL23的产生的机制。都是 此法规涉及的UPR和TLR4途径？ 2）什么是生化和结构基础 CNPY2在促进TLR4信号依赖性细胞因子产生巨噬细胞中的作用。解决晶体结构 CNPY2的of将有助于针对CNPY2的药物开发。 3）CNPY2调节的潜在机制 HCC中肿瘤相关巨噬细胞的分化，浸润和功能。 4）角色是什么 肿瘤免疫史中的CNPY2？靶向CNPY2是否可以改善HCC中的抗肿瘤免疫史地？我们的传统 有条件的CNPY2 KO小鼠是解决这些问题的独特模型。成功执行 工作将大大推动整个领域。从长远来看，这项研究可能为 基于CNPY2抑制剂的合理设计，开发了新的癌症理论理论 肿瘤相关的巨噬细胞。