Structural Basis of Molecular Mechanisms in Cell Guidance and Adhesion.

多细胞有机体的细胞，如人类，在发育过程中要经过精心的编排。在发育中的生物体中，每个细胞必须在特定的时间和地点达到与其角色相适应的粘附性和运动性之间的特殊平衡。指导每个细胞的许多信息必须通过与其邻近环境包括邻近细胞的相互作用而获得。这些相互作用是由嵌入在细胞表面的各种类型的受体分子介导的。我们希望了解一个分子家族，信号素，是如何与它们的受体神经丛一起工作，控制细胞粘着(粘连)或向特定方向移动的能力。利用结构生物学技术，我们的目标是以原子细节揭示信号素和丛蛋白控制细胞黏附和引导的机制，例如在指导大脑连接方面。这些机制必须整合发生在细胞之间和同一细胞表面上的受体相互作用，以及从细胞外环境到细胞内环境的相互作用。为了深入了解这种系统，我们需要使用最先进的技术来生产合适的信号素、丛及其复合体样本，并将对分离分子的体外结构研究与细胞表面功能相关背景下的原位分析相结合。这是对生物学构建神经系统和血管、维持骨骼和激活免疫系统的机制的基础研究。通过了解这些机制，我们也将更好地探索可能导致脊髓损伤后切断的神经无法再生的分子因素，导致骨相关疾病(如骨质疏松症)、神经发育障碍(如自闭症障碍谱)和癌症的分子因素。最终，生物技术和制药行业可以利用这些知识，为新疗法的设计提供信息和指导。

The cells of a multicellular organism, such as a human, are subject to an exquisite choreography during development. Each cell must achieve the particular balance between adhesion and motility appropriate to its role at a specific time and place in the developing organism. Much of the information to direct each cell must be garnered through interaction with its immediate environment including neighbouring cells. These interactions are mediated by various types of receptor molecules embedded in the cell surface. We wish to understand how one family of molecules, the semaphorins, work together with their receptors, the plexins, to control the ability of a cell to stick (adhere) or to move in a specific direction. Using the techniques of structural biology we aim to uncover, in atomic detail, the mechanisms by which the semaphorins and plexins control cell adhesion and guidance, for example in directing the wiring of the brain. These mechanisms must integrate receptor interactions occurring between cells and on the same cell surface, as well as spanning from the extracellular to the intracellular environment. To generate insight into such systems we will need to use state of the art techniques to produce suitable samples of the semaphorins, the plexins and their complexes, and to combine in vitro structural studies on the isolated molecules with in situ analyses in the functionally relevant context of the cell surface. This is basic research into the mechanisms by which biology works to build the nervous system and the blood vessels, to maintain bones and to activate the immune system. By understanding these mechanisms we will also be better equipped to explore molecular factors which may contribute to the failure of severed nerves to regenerate following spinal cord injury, to bone-related disorders, for example osteoporosis, to neurodevelopmental disorders such as autism disorder spectrum, and to cancer. Ultimately this knowledge can be used by the biotechnology and pharmaceutical industries, to inform and guide the design of novel therapeutics.