FIBRIN(OGEN) STRUCTURE AND INTERACTIONS

（研究者摘要）：纤维蛋白原是一种多功能蛋白 参与了许多重要的生理和病理过程 流程.在组织损伤部位（或组织损伤部位）形成法布蛋白基质（fabrin matrix）。 其他部位）防止失血并提供临时基质， 与不同类型的细胞相互作用以促进它们的沉积、迁移 和扩散。因此，除了具有显著的止血作用外， 纤维蛋白原被认为是一种细胞粘附分子， 在炎症、血管生成、伤口愈合、动脉粥样硬化形成中的重要作用 和肿瘤发生。尽管有许多研究，但一些基本问题 对于全面了解其生物学功能至关重要 仍然悬而未决本申请涉及三个这样的问题：（1） 高分辨率结构，（2）转换的分子机制 纤维蛋白原的纤维蛋白，和（3）的相互作用机制， Fabrin（ogen）与不同的细胞类型。第一个目标是建立 纤维蛋白原E区的高分辨结构及其与纤维蛋白原的关系 α-C结构域。第二个目的是阐明 假设纤维蛋白原转化为法布蛋白涉及一种转换， 从α-C结构域之间的分子内到分子间结合， 在D区的构象变化，调节活性的 二次聚合位点和新的相互作用位点的表达。 第三个目标侧重于建立互动机制， 内皮细胞和白细胞与纤维蛋白原和纤维蛋白， 鉴定所涉及的关键氨基酸残基。这些目标将 通过制备各种纤维蛋白原结构域来实现， 通过有限的蛋白水解和重组技术将其组合， 并通过生物化学和 生物物理方法。这些研究将产生基本知识， 对理解和控制不同的 纤维蛋白原依赖性过程。他们还将有一个重要的实际 与健康相关的应用，以开发改进的生物粘合剂 （纤维蛋白胶）通过具有选定功能的纤维蛋白原的从头设计。

(Investigator's abstract): Fibrinogen is a multifunctional protein involved in a number of important physiological and pathological processes. The formation of a fabrin matrix at sites of tissue injury (or other places) prevents blood loss and provides a provisional stroma that interacts with different cell types to promote their deposition, migration and proliferation. Thus, besides its prominent function in hemostasis, fibrinogen is recognized as a cell adhesion molecule that plays an important role in inflammation, angiogenesis, wound healing, atherogenesis and tumorigenesis. Despite numerous studies, several basic problems important for a comprehensive understanding of its biological functions are still unresolved. This application deals with three such problems: (1) a high resolution structure, (2) the molecular mechanisms of conversions of fibrinogen to fibrin, and (3) the mechanisms of interactions of fabrin(ogen) with different cell types. The first aim is to establish the high resolution structure of the central E regions of fibrinogen and its alpha-C domains. The second aim is to elucidate the mechanisms of fibrinogen to fabrin conversions which is hypothesized to involve a switch from intra- to intermolecular binding between alpha-C domains as well as conformation changes in the D region that modulate activity of the secondary polymerization sites and expression of new interaction sites. The third aim focuses on establishing the mechanisms of interaction of endothelial cells and leukocytes with fibrinogen and fibrin and identification of critical amino acid residues involved. These aims will be accomplished by preparation of various fibrinogen domains and combinations there of by limited proteolysis and recombinant techniques, and studying their structures and interactions by biochemical and biophysical methods. These studies will generate basic knowledge that will have an impact on the understanding of and ability to control different fibrinogen-dependent processes. They will also have an important practical health-related application to the development of improved bioadhesives (fibrin glue) by the de novo design of fibrinogen with selected functions.