STRUCTURE AND FUNCTION OF THE INTEGRIN ALPHA1 BETA1

拟议研究计划的主要目标是调查 细胞控制与细胞外相互作用的机制 基质和基底膜在移行和分化过程中的作用 正常和疾病状态。整合素受体异二聚体α1-β1， 层粘连蛋白/胶原蛋白受体被选为这一研究的模型系统 学习是因为有几个独特的特点。这个分子有一个有限的 体内分布，存在于激活的淋巴细胞、神经元上 到目前为止所研究的成人组织中的肾脏细胞和系膜。 这种分布意味着一种选择性和特定的功能，而不是 由其他整合素胶原/层粘连蛋白受体(即α2，3和 6)。这种整合素可以在淋巴细胞表面被诱导 体外激活、体外激活PC12细胞、体内激活滑膜 类风湿关节炎患者的淋巴细胞。因此，这个分子 可能在体内受到严格的调控，并使我们能够研究控制 整合素的功能。人整合素α1亚单位的cDNA克隆 将用于生产融合蛋白和合成肽 抗体的产生。Alpha1在提供位置信息中的作用 细胞迁移中对正常发育至关重要的信息将是 通过确定表达的时间和空间模式进行调查 在哺乳动物胚胎中起诉这些探针。尤其是，出现了 这种迁移细胞上的整合素将使我们能够确定是否存在 表达水平从发育早期的变化，当细胞 当它们到达目的地时，迁徙到很晚。最后，这一点 整合素在不同的细胞类型上表现出不同的配体特异性， 结合一些层粘连蛋白和胶原蛋白，而只结合胶原蛋白 其他，允许调查这两个因素的财产 影响细胞内配体特异性的Alpha1的内源性和外源性 体内的迁移。这些因素将使用完整、截断 和分子的突变形式，后两者是通过定点产生的 诱变和异源真核表达系统。这项研究 将增强我们对两种细胞迁移机制的了解 发育等正常状态和肿瘤细胞等异常状态 转移和慢性炎症性疾病；长期目标是 确定α1和其他整合素在靶向靶向中的作用 处于疾病状态的细胞。

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.