VASCULAR CELL GROWTH AND MATRICELLULAR PROTEINS

血小板反应蛋白2 （TSP2）和SPARC是作为细胞功能的细胞外调节因子的基质细胞蛋白。这些蛋白质调节各种细胞的形状和粘附、迁移、合成和增殖活动。因此，由于内源性基因的靶向突变而缺乏TSP2和SPARC的小鼠在多种基本生物学特性和过程中表现出异常，包括细胞外基质的组成和结构、对损伤的反应、骨骼生长、血管发育和生长以及止血。该应用的重点是基质细胞蛋白对血管生长的调节。因此，将设计实验来回答以下问题。1) TSP2作为血管生成抑制剂的作用方式的分子基础是什么？2) sparc缺失小鼠是否表现出异常的血管生成和/或血管生成？3)。SPARC同源物SC1是否部分或完全补偿SPARC在SPARC缺失小鼠血管形态发生中的作用？4)在缺乏两种血管生成抑制剂TSP2和SPARC的小鼠中，与脉管系统或结缔组织相关的表型是否会加剧？这些问题的答案将为控制血管形成提供重要的新信息。此外，这些实验有可能发展出一种方法，通过这种方法可以改善皮肤伤口的愈合，并改变异物对植入生物材料的反应，从而使通常无血管的被膜血管化。

Thrombospondin 2 (TSP2) and SPARC are matricellular proteins that act as extracellular regulators of cellular function. These proteins modulate the shape and adhesion, and the migratory, synthetic and proliferative activities of a variety of cells. As a consequence, mice that lack TSP2 and SPARC as a result of targeted mutations of the endogenous genes display abnormalities in a wide variety of fundamental biological characteristics and processes, including the composition and structure of the extracellular matrix, the response to injury, bone growth, blood vessel development and growth, and hemostasis. The focus of this application is the regulation of vascular growth by matricellular proteins. Experiments to answer the following questions will therefore be designed. 1) What is the molecular basis for the mode of action of action of TSP2 as a inhibitor of angiogenesis? 2) Do SPARC-null mice exhibit abnormal angiogenesis and/or vasculogenesis? 3.) Does the SPARC homolog, SC1, compensate partially or fully for SPARC in the morphogenesis of the vasculature in SPARC-null mice? 4) Will phenotypes relating to vasculature, or to connective tissue, be exacerbated in mice lacking two inhibitors of angiogenesis, TSP2 & SPARC? The answers to these questions will provide important new information regarding the control of blood vessel formation. In addition, these experiments have the potential to develop a means by which the healing of skin wounds can be improved, and the foreign body reaction to implanted biomaterials modified, such that the normally avascular capsule is vascularized.