VASCULAR CELL GROWTH AND MATRICELLULAR PROTEINS

凝血酶敏感蛋白2(TSP2)和SPARC是细胞外调节细胞功能的基质蛋白。这些蛋白质调节各种细胞的形态和黏附，以及迁移、合成和增殖活动。因此，由于内源性基因的靶向突变而导致缺乏TSP2和SPARC的小鼠，在广泛的基本生物学特征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。这一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作为血管生成抑制因子作用方式的分子基础是什么？2)SPARC基因缺失的小鼠是否存在血管生成和/或血管生成异常？在SPARC缺失的小鼠中，SPARC同源基因SC1是否部分或全部补偿了SPARC在血管系统的形态发生中的作用？4)在缺乏两种血管生成抑制剂TSP2和SPARC的小鼠中，与血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血管形成的控制提供重要的新信息。此外，这些实验有可能开发出一种方法，通过这种方法可以改善皮肤伤口的愈合，并修改对植入的生物材料的异物反应，从而使正常的无血管囊膜血管化。

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.