The a2b1 Integrin: Innate Immunity to Pathogens & Tumors

描述(申请人提供)：a2a1整合素是一种胶原/层粘连蛋白受体，表达在血小板、内皮细胞、成纤维细胞、上皮细胞和白细胞亚群上。为了确定a2a1整合素在体内的作用，我们创造了一个基因工程小鼠，在其中a2a1整合素的表达完全消除。缺乏a2a1整合素的小鼠可以存活和生育，发育相对正常。乳腺分支形态发生的定量分析表明，在a2缺乏的动物中，分支的复杂性明显降低。虽然a2基因缺陷的小鼠没有表现出出血素质，但a2基因缺失的小鼠的血小板在静态或剪切应力条件下都不能与I型胶原粘连。因此，a2a1整合素缺失的小鼠表现出多样的、有时微妙的表型，与广泛存在的整合素表达模式一致。 白细胞整合素是免疫系统发育和激活所必需的，也是白细胞迁移到损伤、感染和肿瘤形成部位所必需的。A2a1整合素此前并未被认为在免疫功能中起主要作用。我们令人兴奋的初步数据清楚地表明，a2a1整合素是对感染性生物和可能的肿瘤的先天免疫所必需的。这一建议将直接解决a2a1整合素表达是先天性免疫功能所必需的假设。其具体目的是(1)以单核细胞增多性李斯特菌为模型，确定a2a1整合素在细菌免疫应答中的作用。(2)明确a2a1整合素介导的MCMV感染免疫应答机制。(3)确定a2a1整合素是否在肿瘤免疫编辑中发挥作用。综上所述，这项提议将确定a2a1整合素表达在针对细菌、病毒和肿瘤的先天免疫反应中的作用。

DESCRIPTION (provided by applicant): The a2a1 integrin is a collagen/laminin receptor expressed on platelets, endothelial cells, fibroblasts, epithelial cells, and subsets of leukocytes. To define the role of the a2a1 integrin in vivo, we created a genetically engineered mouse in which expression of the a2a1 integrin was completely eliminated. Mice deficient in the a2a1 integrin are viable and fertile and develop relatively normally. Quantitative analysis of mammary gland branching morphogenesis demonstrated that branching complexity is markedly diminished in the a2-deficient animals. Although the a2-deficient mice do not manifest a bleed diathesis, platelets from a2-null mice fail to adhere to type I collagen under either static or shear-stress conditions. The a2a1 integrin-null mouse thus exhibits diverse, sometimes subtle, phenotypes consistent with the widespread pattern of integrin expression. Leukocyte integrins are required for development and activation of the immune system and for leukocyte migration to sites of injury, infection, and tumor formation. The a2a1 integrin has not previously been considered to play a major role in immune function. Our exciting preliminary data clearly demonstrate that the a2a1 integrin is required for innate immunity to infectious organisms and possibly tumors. This proposal will directly address the hypothesis that a2a1 integrin expression is required for innate immune function. The specific aims are (1) To define the role of the a2a1 integrin in the immune response to bacteria using Listeria monocytogenes as a model. (2) To define the mechanisms involved in a2a1 integrin mediated immune response to MCMV infection. (3) To determine whether the a2a1 integrin plays a role in tumor immunoediting. In summary, this proposal will determine the role of the a2a1 integrin expression in the innate immune response to bacteria, viruses, and tumors.