Extracellular Matrix in Mice Lacking Thrombospondin 2

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DESCRIPTION (provided by applicant): Thrombospondin 2 (TSP2) is an extracellular protein that modulates cell functions such as adhesion, migration, and proliferation by its ability to interact with growth factors, cytokines, proteases, and a large number of cell-surface receptors. Mice that lack TSP2 display a number of seemingly unrelated defects including abnormally structured collagen fibrils, reduced fibroblast adhesion, a bleeding disorder, and a response to injury that is characterized by increased vascularity. The purpose of this proposal is to understand how this diverse phenotype can result from the absence of a single protein. More fundamentally, we expect to learn more about the role of proteases in cell adhesion, the control of angiogenesis and bone growth, the factors involved in normal platelet formation and aggregation, and the course of wound healing. Planned experiments include: 1) studies of the interaction of a matrix metalloproteinase, MMP2, with TSP2 and the cell surface; 2) the role of MMP2 in the foreign body response; 3) platelet formation and interaction with the sub-endothelium; 4) the mechanism of inhibition of angiogenesis and bone growth by TSP2, i.e. by apoptosis versus by inhibition of cell proliferation; and 5) an evaluation of the phenotype of TSP 1 /TSP2 double-null mice, and of the contribution of the lack of each protein to the phenotype as determined by local gene therapy. These experiments have the potential to develop the means to improve wound healing, and the performance of implanted biosensors and delivery devices, in human subjects.