The alpha2beta1 Integrin: Innate Immunity to Pathogens & Tumors

描述（由申请人提供）：α 2 α 1整联蛋白是在血小板、内皮细胞、成纤维细胞、上皮细胞和白细胞亚群上表达的胶原/层粘连蛋白受体。为了确定α 2 α 1整联蛋白在体内的作用，我们建立了一个基因工程小鼠，其中α 2 α 1整联蛋白的表达被完全消除。缺乏a2 a1整联蛋白的小鼠是有活力的，可生育的，发育相对正常。乳腺分支形态发生的定量分析表明，在α 2缺陷动物中，分支的复杂性显著降低。虽然α 2缺陷小鼠没有表现出出血素质，但在静态或剪切应力条件下，来自α 2缺失小鼠的血小板未能粘附到I型胶原。因此，a2 a1整合素缺失小鼠表现出与整合素表达的广泛模式一致的多样的，有时是微妙的表型。 白细胞整联蛋白是免疫系统的发育和激活以及白细胞迁移至损伤、感染和肿瘤形成部位所必需的。α 2 α 1整联蛋白以前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，α 2 α 1整合素是对感染性生物体和可能的肿瘤的先天免疫所必需的。这一提议将直接解决α 2 α 1整合素表达是先天免疫功能所必需的这一假设。具体目的是（1）使用单核细胞增生李斯特菌作为模型来确定α 2 α 1整联蛋白在对细菌的免疫应答中的作用。(2)目的探讨α 2 α 1整合素介导的抗MCMV免疫应答的机制。(3)确定α 2 α 1整合素是否在肿瘤免疫编辑中发挥作用。总之，该提议将确定α 2 α 1整联蛋白表达在对细菌、病毒和肿瘤的先天免疫应答中的作用。

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.