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.
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