(taken from the application): Thrombospondin 2 (TSP2) is an extracellular protein whose functions are complex and poorly understood. Two lines of mice that lack TSP2 have been generated by homologous recombination in embryonic stem cells. These mice display a wide spectrum of connective tissue and cellular abnormalities, including fragile skin, abnormal fibrils in skin and tendon, skin fibroblasts with adhesive defects, lax tendons and ligaments and increased bone density. The mice also have a marked increase in vascular density and a bleeding tendency, findings which might also have a basis in the extracellular matrix. The proposed work will focus on: 1) the nature of the adhesive defects in fibroblasts; the contributions of the substratum and of cell-surface receptors from ECM proteins will be examined; (2) the molecular basis for the increased fragility of skin and the presence of abnormal collagen fibrils in connective tissues; approaches will include immunofluorescence analyses and transmission, scanning and immunogold electron microscopy; 3) the underlying cause for the increased bone density in TSP-null nice; possible defects in bone resorption and synthesis will be assessed; 4) the bleeding diathesis; a role for TSP2 in stabilizing the tethering of platelets to the sub-endothelium will be examined; 5) studies of wound healing and subcutaneous sponge implants. This work may therefore have significant implications for studies of matrix synthesis and assembly, bone growth, and homeostasis. Moreover, the elucidation of the role of TSP2 in these diverse processes is likely to reveal previously unsuspected functions for TSP2 and related proteins in connective tissue.
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