MULTIDISCIPLINARY STRUCTURES AT VASCULAR CELL SURFACES

描述（由申请人提供）：血管细胞粘附相互作用在健康和疾病中是重要的，从血栓形成和动脉粥样硬化到血管炎和癌症。包括整联蛋白在内的粘附分子和包括粘着斑激酶（FAK）和免疫受体在内的信号传导分子是所有这些过程的关键，并且是目前批准和正在开发的药物的重要靶标。该计划整合了在原子和细胞水平上对血管系统中细胞粘附和信号传导的研究，其总体目标是加速获得新知识和开发治疗疾病的药物。它将一群在哈佛医学长木地区有着悠久合作和互动历史的研究人员联系在一起。研究人员在广泛的结构生物学技术，包括晶体学，EM和NMR方面具有专业知识，能够采用多学科方法解决重要的生物学问题。此外，专业知识包括细胞外，膜和细胞质环境。具有不同结构技术和不同细胞环境专业知识的研究人员之间的相互作用为理解跨质膜由外向内和由内向外方向的信号传导提供了重要的协同作用。项目1（Springer）研究了aIphalB 3的结构和激活机制，其与小分子和大分子（包括纤维蛋白原和Del-1）的复合物，以及免疫性血小板减少性紫癜的结构基础。项目2（Springer）侧重于通过α 4 B1和α 4 B7整联蛋白与配体MAdCAM-1和VCAM-1的相互作用以及与候选治疗性抗体和小分子的复合物进行滚动和牢固粘附的分子基础。项目3（Wang）定义了白细胞整联蛋白aM和aXI结构域与配体C3 bi、ICAM-1和Del-1结合的结构基础。项目5（Chou）定义了免疫受体家族的两个原型成员（DAP 12）2（NKG 2C）1和sigma 2（NKp 46）1的膜嵌入三联体结构。项目6（Eck）通过使用结构、细胞生物学和小分子来检查粘着斑的信号传导，并探索磷脂酰肌醇磷酸对FAK酪氨酸激酶的激活。管理（Springer）和蛋白表达（Lu）核心增强PPG的效率。(End摘要）

DESCRIPTION (as provided by applicant): Vascular cell adhesive interactions are important in health and diseases ranging from thrombosis and atherosclerosis to the vasculitides and cancer. Adhesion molecules including integrins, and signaling molecules including focal adhesion kinase (FAK) and immune receptors, are key in all of these processes, and are important targets of drugs currently approved and under development. This Program integrates studies at the atomic and cellular level on cell adhesion and signaling in the vasculature, with the overall aim of accelerating both the acquisition of new knowledge and the development of drugs to treat disease. It ties together a group of investigators with a long history of collaboration and interaction in the Harvard Medical Longwood Area. The investigators have expertise in a wide range of structural biology techniques including crystallography, EM, and NMR, enabling a multidisciplinary approach to solving important biological problems. Furthermore, expertise includes the extracellular, membrane, and cytoplasmic environments. The interactions between investigators with expertise in different structural techniques and different cellular environments provide important synergies between the projects in understanding signaling in the outside-in and inside-out directions across the plasma membrane. Project 1 (Springer) examines the structure and mechanism of activation of aIphalB3, its complexes with small molecules and macromolecules including fibrinogen and Del-1, and the structural basis for immune thrombocytopenic purpura. Project 2 (Springer) focuses on the molecular basis for rolling and firm adhesion through interaction of alpha4B1 and alpha4B7 integrins with ligands MAdCAM-1 and VCAM-1, and complexes with candidate therapeutic antibodies and small molecules. Project 3 (Wang) defines the structural basis for binding of leukocyte integrin aM and aX I domains to ligands C3bi, ICAM-1, and Del-1. Project 5 (Chou) defines the membrane-embedded triad structures of two archetypal members of the immune receptor family, (DAP12)2(NKG2C)1 and sigma2(NKp46)1. Project 6 (Eck) examines signaling at focal adhesions and explores activation of the tyrosine kinase of FAK by phosphatidylinositol phosphates through use of structures, cell biology, and small molecules. Administrative (Springer) and Protein Expression (Lu) Cores enhance efficiency of the PPG. (End of Abstract)