(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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR045418-01
Application #
2681754
Study Section
Special Emphasis Panel (ZRG3-SSS-2 (03))
Project Start
1998-07-15
Project End
2002-06-30
Budget Start
1998-07-15
Budget End
1999-06-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Washington
Department
Biochemistry
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Reinecke, Hans; Robey, Thomas E; Mignone, John L et al. (2013) Lack of thrombospondin-2 reduces fibrosis and increases vascularity around cardiac cell grafts. Cardiovasc Pathol 22:91-5
MacLauchlan, Susan; Skokos, Eleni A; Meznarich, Norman et al. (2009) Macrophage fusion, giant cell formation, and the foreign body response require matrix metalloproteinase 9. J Leukoc Biol 85:617-26
Kyriakides, Themis R; Wulsin, Drausin; Skokos, Eleni A et al. (2009) Mice that lack matrix metalloproteinase-9 display delayed wound healing associated with delayed reepithelization and disordered collagen fibrillogenesis. Matrix Biol 28:65-73
Maclauchlan, Susan; Skokos, Eleni A; Agah, Azin et al. (2009) Enhanced angiogenesis and reduced contraction in thrombospondin-2-null wounds is associated with increased levels of matrix metalloproteinases-2 and -9, and soluble VEGF. J Histochem Cytochem 57:301-13
Gruber, Helen E; Bornstein, Paul; Sage, E Helene et al. (2008) Disruption of the thrombospondin-2 gene alters the lamellar morphology but does not permit vascularization of the adult mouse lumbar disc. Arthritis Res Ther 10:R96
Posey, Karen L; Hankenson, Kurt; Veerisetty, Alka C et al. (2008) Skeletal abnormalities in mice lacking extracellular matrix proteins, thrombospondin-1, thrombospondin-3, thrombospondin-5, and type IX collagen. Am J Pathol 172:1664-74
Oganesian, Anush; Armstrong, Lucas C; Migliorini, Mary M et al. (2008) Thrombospondins use the VLDL receptor and a nonapoptotic pathway to inhibit cell division in microvascular endothelial cells. Mol Biol Cell 19:563-71
Daniel, Christoph; Amann, Kerstin; Hohenstein, Bernd et al. (2007) Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in experimental glomerulonephritis in mice. J Am Soc Nephrol 18:788-98
Lamy, Laurence; Foussat, Arnaud; Brown, Eric J et al. (2007) Interactions between CD47 and thrombospondin reduce inflammation. J Immunol 178:5930-9
Kopp, Hans-Georg; Hooper, Andrea T; Broekman, M Johan et al. (2006) Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization. J Clin Invest 116:3277-91

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