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

描述(申请人提供)：结肠癌是美国癌症相关死亡的主要原因。众所周知，接触一些有害的环境物质和食用西方饮食是导致恶性结肠癌的原因之一。虽然慢性炎症已知是肿瘤发展的主要促进因素，但肠道菌群在结肠癌中的作用尚不清楚。我们的实验室已经确定白三烯B4受体BLT1是炎症和宿主对感染反应的主要调节因子。在自发性肠癌的小鼠模型(ApcMin/)中，我们观察到BLT1的缺失极大地促进了肠道肿瘤的发展。这导致了一个中心假说，即BLT1的缺失通过缺陷的免疫监视和/或改变微生物肠道稳态来促进结肠癌的发展。这一明显自相矛盾的结果表明，肠道微环境的不断变化可能对结直肠癌的发展产生重大影响。目前的提案将在三个具体目标上检验这一假设。在目标1中，我们将研究白三烯B4途径介导的对ApcMin/小鼠肠癌的保护机制。目的2将在BLT1/和BLT1-/-小鼠的背景下建立荷瘤小鼠的免疫功能。目的3将测试这一新概念，即宿主反应缺陷和肠道微生物区系改变是导致BLT1-/-小鼠结肠癌快速发展的原因。这些研究将提供一个全面的模型系统，以检验炎症和感染对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，其结果将对人类结肠癌的治疗产生直接和立竿见影的影响。公共卫生相关性：白三烯参与许多急慢性炎症性疾病的病理生理学，如全身过敏反应、哮喘、动脉粥样硬化和关节炎。白三烯B4-白三烯B4受体1轴可能在结肠癌的发生发展中起保护作用，这一新发现为理解这些介质在肿瘤发生中的作用提供了一个独特的机会。了解小鼠体内不同的白三烯B4受体的确切功能，并确定这些受体在宿主防御和塑造肠道微生物区系中的作用，将为结肠癌的治疗提供新的方法。

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.