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Lung tumor associated macrophages

肺肿瘤相关巨噬细胞

基本信息

批准号：
7802963
负责人：
ALVIN M MALKINSON
金额：
$ 29.09万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-17 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7802963
关键词：
A/J Mouse Affect Alveolar Alveolar Macrophages Anabolism Animal Model Apoptosis Arginine Atlas of Cancer Mortality in the United States Bacterial Infections Behavior Bone Marrow Bone Marrow Transplantation Cell Line Cell Proliferation Cells Chronic Coculture Techniques Development Diagnosis Epithelial Epithelial Cells Exposure to Gene Expression Genes In Vitro Inflammation Inflammation Mediators Inflammatory Inflammatory Response Left Leukocytes Liquid substance Lung Lung Neoplasms Macrophage Activation Malignant - descriptor Malignant neoplasm of lung Marrow Mediator of activation protein Metabolism Modeling Modification Molecular Mus Nature Neoplasms Nitric Oxide Oncogenes Phenotype Physiological Play Polyamines Population Predisposition Primary Carcinoma Prostaglandins Role Series Signal Pathway Signal Transduction Site Stem cells Susceptibility Gene Testing Therapeutic Intervention Tissues Urethane adaptive immunity adenoma arginase carcinogenesis cell behavior cell motility chemical carcinogen chemical carcinogenesis cytokine human NOS2A protein in vivo lung injury lung tumorigenesis macrophage monocyte mouse model mutant neoplastic novel research study respiratory response tumor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): The key leukocytes associated with chronic inflammation are macrophages. Macrophages play an important role in the development of lung tumors from initiated cells in lung cancer and in experimental respiratory carcinogenesis. We propose a series of in vivo modulations of macrophage activation to determine how these inflammatory phenotypes affect lung tumorigenesis in mouse models. Among the manipulations are exogenous addition of cytokines, bone marrow transplants of genetically distinct marrow populations, varying the number and activation status of pulmonary macrophages during chemical carcinogenesis, as well as using conditional lung-targeted oncogene induction of neoplasia. The macrophage activation states we will examine have distinct physiological roles. M1 activation results from bacterial infection, while M2 activation is key in adaptive immunity. To distinguish between these two phenotypes, we examine arginine metabolism. M1 activation is characterized by inducible nitric oxide synthase expression which results in arginine metabolism to citruline and nitric oxide while M2 activation results in arginase expression leading to polyamine biosynthesis. We will investigate in vitro co-culture models varying lung epithelial and macrophage composition. We will thus deduce which macrophage activation states can modify lung epithelial cell behavior, and examine how epithelial cells at different states of neoplasia affect macrophages. These experiments will provide a molecular understanding of how inflammation promotes lung cancer.

描述(申请人提供)：与慢性炎症相关的关键白细胞是巨噬细胞。巨噬细胞在肺癌的起始细胞和实验性呼吸道癌的发生发展过程中起重要作用。我们提出了一系列巨噬细胞激活的体内调节机制，以确定这些炎症表型如何影响小鼠模型的肺肿瘤发生。这些操作包括细胞因子的外源性添加，对遗传上不同的骨髓群体进行骨髓移植，在化学致癌过程中改变肺巨噬细胞的数量和激活状态，以及使用有条件的肺靶向癌基因诱导肿瘤。我们将研究的巨噬细胞激活状态具有不同的生理作用。M1的激活是细菌感染的结果，而M2的激活是获得性免疫的关键。为了区分这两种表型，我们检测了精氨酸代谢。M1的激活以诱导型一氧化氮合酶的表达为特征，导致精氨酸代谢为瓜氨酸和一氧化氮，而M2的激活导致精氨酸酶的表达，从而导致多胺的生物合成。我们将研究不同肺上皮细胞和巨噬细胞组成的体外共培养模型。因此，我们将推断哪些巨噬细胞激活状态可以改变肺上皮细胞的行为，并研究处于不同肿瘤状态的上皮细胞如何影响巨噬细胞。这些实验将提供对炎症如何促进肺癌的分子理解。