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很重要，从血栓和动脉粥样硬化到血管粥样硬化和癌症。包括整合素在内的粘附分子和包括局点粘附激酶（FAK）和免疫受体在内的信号分子是所有这些过程的关键，也是目前已批准和正在开发的药物的重要靶点。该计划整合了在原子和细胞水平上对血管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。它将一组在哈佛医学院朗伍德地区有着长期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方面拥有专业知识，包括晶体学，EM和NMR，使多学科方法能够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，为了解质膜上由外向内和由内向外方向的信号提供了重要的协同作用。项目1（施普林格）研究了aIphalB3及其与纤维蛋白原、Del-1等小分子和大分子复合物的结构和激活机制，以及免疫性血小板减少性紫癜的结构基础。项目2（施普林格）侧重于通过alpha4B1和alpha4B7整合素与配体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，研究滚动和牢固粘附的分子基础。Project 3 （Wang）定义了白细胞整合素aM和aX I结构域与配体C3bi、ICAM-1和Del-1结合的结构基础。Project 5 （Chou）定义了免疫受体家族的两个原型成员（DAP12）2(NKG2C)1和sigma2(NKp46)1的膜内三联结构。项目6 （Eck）通过使用结构、细胞生物学和小分子，研究了局灶黏附的信号传导，并探索了磷脂酰肌醇磷酸对FAK酪氨酸激酶的激活。管理核（施普林格）和蛋白表达核（Lu）提高了PPG的效率。（摘要结束）

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)