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.

摘要 肝癌是最常见的癌症类型之一。超过70万人被诊断患有这种疾病 癌症每年在世界各地。肝癌是负责超过30，000新病例和12，000 美国每年死亡人数。已经发现肝癌与ER应激/未折叠高度相关 蛋白质反应（UPR）诱导的慢性炎症;然而，其机制仍不清楚。 使用遗传学方法，我们发现从巨噬细胞中删除ER蛋白CNPY 2， 致癌物诱导的肝细胞癌，伴有ER应激/UPR信号减少和肿瘤- 相关的巨噬细胞。此外，CNPY 2是促炎细胞因子IL 6和IL 10所必需的。 枯否细胞/肝巨噬细胞释放的TNFα。我们还观察到CNPY 2在以下方面起着核心作用： 调节ER应激/UPR和TLR 4信号传导，这两种途径已知促进细胞因子产生， 巨噬细胞的分化。总之，这些观察结果表明，CNPY 2促进肝脏肿瘤发生 通过调节巨噬细胞。 在这份提案中，我将致力于解决HCC领域的几个基本问题：1）什么是 CNPY 2转录调节巨噬细胞中IL 6和IL 23产生的机制。都是 UPR和TLR 4通路参与了这一调节？2)生物化学和结构基础是什么 CNPY 2在促进巨噬细胞中TLR 4信号传导依赖性细胞因子产生中的作用。解析晶体结构 CNPY 2的表达将有助于针对CNPY 2的药物开发。3)CNPY 2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)的作用是什么 CNPY 2与肿瘤免疫靶向CNPY 2是否改善HCC中的抗肿瘤免疫？我们传统 而条件性Cnpy 2 KO小鼠是解决这些问题的独特模型。成功执行本 这项工作将极大地推动该领域的发展。从长远来看，这项研究可能会奠定坚实的基础， 基于CNPY 2抑制剂的合理设计，开发了一类新的癌症治疗药物， 肿瘤相关巨噬细胞。