The a2b1 Integrin: Innate Immunity to Pathogens & Tumors

描述（由申请人提供）：a2a1整合素是一种胶原/层粘连蛋白受体，在血小板、内皮细胞、成纤维细胞、上皮细胞和白细胞亚群上表达。为了确定a2a1整合素在体内的作用，我们创造了一只完全消除a2a1整合素表达的基因工程小鼠。缺乏a2a1整合素的小鼠可以存活和生育，并且发育相对正常。乳腺分支形态发生的定量分析表明，a2缺陷动物的分支复杂性明显降低。虽然缺乏a2的小鼠不表现出出血素质，但来自a2缺失小鼠的血小板在静态或剪切应力条件下都不能粘附在I型胶原蛋白上。因此，a2a1整合素缺失小鼠表现出多样化，有时是微妙的，与整合素广泛表达模式一致的表型。

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.