STRUCTURE AND FUNCTION OF THE INTEGRIN ALPHA1 BETA1

拟议研究计划的主要目标是调查 细胞控制其与细胞外 基质和基底膜在迁移和分化过程中的作用 正常和疾病状态。 整联蛋白受体异源二聚体α 1-β 1， 层粘连蛋白/胶原蛋白受体，已被选为模型系统， 研究，因为有几个独特的功能。 这种分子具有有限的 体内分布，存在于活化的淋巴细胞上，神经元 细胞和系膜中的成年组织研究的日期。 这种分布意味着一种选择性和特定的功能， 由其它整合素胶原/层粘连蛋白受体实现（即，α 2，3，和 6）。 这种整合素可以在淋巴细胞表面被诱导， 体外激活、体外对PC12细胞的激活和体内对滑膜的激活 类风湿性关节炎患者的淋巴细胞 因此，这种分子 可能在体内受到严格调控，使我们能够研究控制 integrin功能。 人整合素α 1亚基的cDNA克隆 将用于生产融合蛋白和合成肽， 产生抗体。 alpha1在提供位置的作用 细胞迁移中对正常发育至关重要的信息， 通过确定表达的时间和空间模式来研究 在哺乳动物胚胎中使用这些探针。 特别是， 这种迁移细胞上的整合素将使我们能够确定 从发育早期开始，当细胞 迁移，到晚了，当他们到达目的地。 最后这 整联蛋白在不同的细胞类型上显示出不同的配体特异性， 在一些上结合层粘连蛋白和胶原，而在另一些上仅结合胶原。 其他人，一个属性，允许调查的因素， 影响细胞中配体特异性α 1内源性和外源性 体内迁移。 这些因素将使用完整的，截断的 和突变形式的分子，后两个产生的定点 诱变和异源真核表达系统。 本研究 将增强我们对细胞迁移机制的认识， 正常状态如发育和异常状态如肿瘤细胞 转移和慢性炎性疾病;长期目标是 确定α 1和其他整合素在靶向中的作用 疾病状态下的细胞。

The main objective of the proposed research plan is to investigate the mechanisms by which cell control their interactions with extracellular matrix and basement membranes during migration and differentiation in the normal and disease state. The integrin receptor heterodimer alpha1-beta1, a laminin/collagen receptor, has been chosen as a model system for this study because of several unique features. This molecular has a limited distribution in vivo, being present on activated lymphocytes, neuronal cells and in the mesangium of the kidney in adult tissues studied to date. This distribution implies a selective and specific function which is not fulfilled by other integrin collagen/laminin receptors (i.e., alpha2,3,and 6). This integrin can be induced on the surface of lymphocytes after activation in vitro, on PC12 cells in vitro, and in vivo on the synovial lymphocytes of patients with rheumatoid arthritis. Thus, this molecule probably is tightly regulated in vivo, and enables us to study the control of integrin function. cDNA clones for the human integrin alpha1 subunit will be used to produce fusion proteins and synthetic peptides for the generation of antibodies. The role of alpha1 in providing positional information in cell migrations crucial to normal development will be investigated by determining the temporal and spatial pattern of expression in mammalian embryos suing these probes. In particular, the presence of this integrin on migrating cells will allow us to determine if there are changes in expression levels from early in development, when the cells are migrating, to late, when they have reached their destination. Lastly, this integrin has shown different ligand specificities on varying cell types, binding laminin and collagen on some, while binding only collagen on others, a property which permits investigation of the factors both intrinsic and extrinsic to alpha1 which affect ligand specificity in cell migrations in vivo. These factors will be studied using intact, truncated and mutant forms of the molecule, the latter two generated by site-directed mutagenesis and heterologous eukaryotic expression systems. This research will enhance our knowledge of the mechanism of cell migration in both normal states such as development, and abnormal states such as tumor cell metastasis, and chronic inflammatory diseases; with the long term goal of determining the role of alpha1 and other integrins in the targeting of cells in disease states.