Role of leukotriene B4 receptors in the interplay of inflammation and infection

白三烯 B4 受体在炎症和感染相互作用中的作用

• 批准号: 8015283
• 负责人: HARIBABU BODDULURI
• 金额: $ 29.67万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015283
• 关键词: APC gene; Acute; Adoptive Transfer; Affinity; Anaphylaxis; Antibiotics; Arthritis; Asthma; Atherosclerosis; Azoxymethane; Biological Models; Bone Marrow; Cancer Etiology; Cancer Model; Cells; Cessation of life; Chimera organism; Chronic; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Consumption; Defect; Development; Diet; Disease; Environment; Environmental Risk Factor; Event; Exposure to; Functional disorder; Genes; Genetic Variation; Health; Homeostasis; Host Defense; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunologic Surveillance; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory disease of the intestine; Integration Host Factors; Intestinal Cancer; Intestinal Neoplasms; Intestines; LTB4R gene; Laboratories; Leukotriene B4; Leukotriene B4 Receptors; Leukotrienes; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular Carcinogenesis; Mus; Mutation; Pathogenesis; Pathway interactions; Phenotype; Play; Process; Proteins; Role; Shapes; Sodium Dextran Sulfate; Testing; Toll-Like Receptor Pathway; Transgenic Mice; Tumor Promoters; United States; airway hyperresponsiveness; base; body system; cell type; environmental agent; gut microbiota; gut microflora; immune function; mRNA Expression; microbial; microbial colonization; microbicide; microorganism interaction; mouse model; novel; novel strategies; protein expression; receptor; tumor

DESCRIPTION (provided by applicant): Colon cancer is a leading cause of cancer related deaths in the United States. Exposure to a number of hazardous environmental agents and consumption of the Western diet are known to contribute to the pathogenesis of malignant colon cancer. While chronic inflammation is known to be a major promoter of tumor development the role of gut microflora in contributing to the colon cancer is unknown. Our laboratory has identified leukotriene B4 receptor, BLT1 as a major regulator of inflammation and host response to infections. In a mouse model of spontaneous intestinal cancer (ApcMin/+), we have made the observation that absence of BLT1 greatly enhances intestinal tumor development. This has led to the central hypothesis that Absence of BLT1 enhances colon tumor development by defective immune surveillance and/or altered microbial gut homeostasis. This apparently paradoxical result that loss of a proinflammatory mediator increases inflammation and tumor development suggests that the ever changing micro environment of intestine can have a major influence on the development of colorectal cancer. The current proposal will test this hypothesis in three specific aims. In aim 1, we will examine the mechanisms of leukotriene B4 pathway mediated protection of intestinal cancers in ApcMin/+ mice. Aim 2 will establish the immune functions in tumor bearing mice in the context of BLT1+/+ and BLT1-/- mice. Aim 3 will test the novel concept that defective host response and altered gut microbiota are responsible for rapid development of colon tumors in BLT1-/- mice. These studies will provide a comprehensive model system to examine the interplay of inflammation and infections to the development of colon cancer. Since the mouse ApcMin/+ model is highly related to human colon cancers the result will have direct and immediate impact for the treatment of human colon cancer. PUBLIC HEALTH RELEVANCE: Leukotrienes are involved in the pathophysiology of many acute and chronic inflammatory diseases such as systemic anaphylaxis, asthma, atherosclerosis and arthritis. The novel finding that leukotriene B4-leukotriene B4 receptor1 axis may have a protective function in the development of colon cancer offers a unique opportunity to understand the role of these mediators in tumor development. Understanding the precise function of distinct leukotriene B4 receptors in mice and defining the role of these receptors in host defense and shaping the gut microflora will provide novel approaches to the treatment of colon cancer.

描述（由申请人提供）：结肠癌是美国与癌症相关死亡的主要原因。众所周知，暴露于许多危险环境药物和西方饮食的消费会导致恶性结肠癌的发病机理。虽然已知慢性炎症是肿瘤发育的主要启动子，但肠道菌群在促进结肠癌中的作用尚不清楚。我们的实验室已将白细胞B4受体BLT1确定为炎症的主要调节剂和对感染的宿主反应。在自发肠癌（APCMIN/+）的小鼠模型中，我们已经观察到，BLT1的缺乏极大地增强了肠道肿瘤的发展。这导致了一个中心假设，即缺乏BLT1通过免疫监测和/或微生物肠内稳态改变会增强结肠肿瘤的发展。这种显然的自相矛盾的结果是，促炎性介质的丧失会增加炎症和肿瘤的发育，这表明肠道不断变化的肠道环境会对结直肠癌的发展产生重大影响。当前的建议将以三个特定目的检验这一假设。在AIM 1中，我们将检查白三烯B4途径的机制介导了APCMIN/+小鼠肠癌的保护。 AIM 2将在BLT1+/+和BLT1 - / - 小鼠的背景下在肿瘤轴承小鼠中建立免疫功能。 AIM 3将测试一个新的概念，即宿主反应和改变的肠道菌群有缺陷，负责BLT1 - / - 小鼠中结肠肿瘤的快速发展。这些研究将提供一个全面的模型系统，以检查炎症和感染与结肠癌发展的相互作用。由于小鼠APCMIN/+模型与人类结肠癌高度相关，因此结果将对人类结肠癌的治疗产生直接和直接的影响。公共卫生相关性：白细胞参与许多急性和慢性炎症性疾病的病理生理，例如全身性过敏反应，哮喘，动脉粥样硬化和关节炎。白细胞B4-丁基三烯B4受体1轴可能在结肠癌发展中具有保护功能的新发现，为了解这些介体在肿瘤发育中的作用提供了独特的机会。了解小鼠中不同白细胞B4受体的精确功能，并定义这些受体在宿主防御中的作用并塑造肠道菌群，将为结肠癌的治疗提供新的方法。