PLATELET GPIIB-IIIA- A MEMBER OF THE CYTOADHESIN FAMILY

血小板 GPIIB-IIIA - 细胞粘附素家族的成员

• 批准号: 3354476
• 负责人: EDWARD Franklin PLOW
• 金额: $ 19.94万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3354476
• 关键词: cell adhesion; cell free system; cobalt; covalent bond; crosslink; fibrinogen; fibrinogen receptors; glycoproteins; human subject; integrins; laboratory mouse; laboratory rabbit; leukocyte adhesion molecules; ligands; molecular site; monoclonal antibody; platelet aggregation; platelets; protein structure function; receptor binding; synthetic peptide; vascular endothelium

This renewal application proposes to continue ongoing studies of the structure and function of integrin (cytoadhesin) adhesion receptors. Integrins, cell-surface heterodimeric molecules, mediate a very broad range of cell-cell and cell-matrix interactions and, thereby, control a diverse set of cellular functions and responses. Two integrins, alpha4/beta1, and alphaM/beta2, have been implicated in many physiological events, including the development of the immune response and hematopoiesis, and pathophysiologic events, including inflammation, reprefusion injury and atherosclerosis. The overall objective of this proposal is to establish the molecular basis for ligand binding to these two integrins as a means of understanding their function. It is further anticipated that insights derived from studies of these two integrins will be broadly applicable and contribute to a general understanding of the ligand binding functions of integrin receptors. Small peptide ligands for alpha4/beta1 and alphaM/beta2 have been identified, and these will be used to define the precise recognition specificities of these two receptors. Covalent crosslinking strategies, similar to those which we have successfully employed to identify ligand recognition sites in alphaIIb/beta3, will then be used to localize sequences within these integrins that mediate ligand binding. Synthetic peptides, monoclonal antibody and mutational strategies will then be brought to bear to definitively establish the role of identified regions in receptor function. Independent strategies, cobalt oxidation to evaluate the role of the metal binding domains and hydropathic complementarity, will also be applied to define the ligand binding mechanisms of alpha4/beta1 and alphaM/beta2. In addition to these studies, a novel hypothesis that fibrinogen functions as a bridging molecule for linking leukocytes to endothelium will be tested. Fibrinogen markedly enhances alphaM/beta2-dependent leukocyte adhesion to endothelial cells, and the molecular and cellular specificity of this effect will be assessed under both static and flowing conditions. By defining the molecular basis for ligand binding functions of alphaM/beta2 and alpha4/beta1 and other integrins and by providing insights into the basis for leukocyte : endothelial cell interactions, which are central to many physiological and pathophysiological processes, our studies have the potential to lead to new approaches to treat inflammation, atherosclerosis and other vascular disorders and diseases.

这种续签应用建议继续对 整联蛋白（细胞粘着蛋白）粘附受体的结构和功能。 整合素，细胞表面异二聚体分子，介导一个非常宽的范围 细胞 - 细胞和细胞 - 矩阵相互作用的相互作用，从而控制多样 一组细胞功能和响应。 两个整合素，Alpha4/beta1，以及 alpham/beta2已与许多生理事件有关，包括 免疫反应和造血的发展，以及 病理生理事件，包括炎症，再灌注损伤和 动脉粥样硬化。 该提议的总体目的是建立 配体与这两个整合素的结合的分子基础作为一种手段 了解他们的功能。 进一步预期的见解 从这两个整合素的研究中得出的将是广泛适用的，并且 有助于对配体结合功能的一般理解 整合素受体。 用于alpha4/beta1的小肽配体和 已经确定了alpham/beta2，这些将用于定义 这两个受体的精确识别特异性。 共价 交联策略，类似于我们成功的 用来识别Alphaiib/beta3中的配体识别站点的工作 用于将介导配体的整合素内定位序列 结合。 合成肽，单克隆抗体和突变策略 然后将被带到明确的角色中 确定的受体功能区域。 独立策略，钴 氧化以评估金属结合结构域的作用和水疗的作用 互补性，也将应用于定义配体结合 alpha4/beta1和alpham/beta2的机制。 除了这些研究， 纤维蛋白原作为桥接分子的新假设 将测试将白细胞与内皮联系起来。 纤维蛋白原明显 增强对内皮细胞的α/beta2依赖性白细胞粘附， 并且将评估该作用的分子和细胞特异性 在静态和流动条件下。 通过定义分子基础 用于alpham/beta2和alpha4/beta1和其他的配体结合功能 通过对白细胞的基础，整合素并提供见解： 内皮细胞相互作用，这对于许多生理和 病理生理过程，我们的研究有可能导致新的 治疗炎症，动脉粥样硬化和其他血管的方法 疾病和疾病。