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。

基本信息

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
项目类别：
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

项目摘要

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类型之一，超过 700,000 人被诊断患有这种癌症。全世界每年有超过 30,000 例新发癌症病例和 12,000 例癌症。美国每年的死亡人数被发现与 ER 应激/未折叠密切相关。蛋白质反应（UPR）引起的慢性炎症；然而，其机制仍不清楚。使用遗传方法，我们发现从巨噬细胞中删除 ER 蛋白 CNPY2 可以防止致癌物诱发的肝细胞癌，伴有 ER 应激/UPR 信号减少和肿瘤- 此外，CNPY2 是促炎细胞因子、IL6 和肿瘤相关巨噬细胞所必需的。我们还观察到 CNPY2 在 Kupffer 细胞/肝巨噬细胞释放的 TNFα 中发挥着核心作用。调节 ER 应激/UPR 和 TLR4 信号传导，这两种途径已知可促进细胞因子的产生和这些观察结果表明 CNPY2 促进肝脏肿瘤发生。通过巨噬细胞的调节。在本提案中，我将致力于解决 HCC 领域的几个基本问题：1）什么是 HCC？ CNPY2 转录调节巨噬细胞中 IL6 和 IL23 产生的机制都是如此。参与此调节的 UPR 和 TLR4 途径 2) 其生化和结构基础是什么？ CNPY2 在促进巨噬细胞中 TLR4 信号依赖性细胞因子产生中的作用 CNPY2的作用将有助于针对CNPY2的药物开发。 3）CNPY2调节的潜在机制。肿瘤相关巨噬细胞在HCC中的分化、浸润和功能。4) 其作用是什么。 CNPY2在肿瘤免疫中的作用？靶向CNPY2是否可以改善我们传统的HCC抗肿瘤免疫？和条件 Cnpy2 KO 小鼠是成功解决这些问题的独特模型。从长远来看，这项工作将显着推进该领域的发展。基于 CNPY2 抑制剂的合理设计，开发一类新型癌症疗法肿瘤相关巨噬细胞。