Tissue repair involves the cellular behaviors and molecular effectors of embryonic morphogenesis, and resembles the host response to invading cancers and metastases. Despite its precise orchestration, tissue repair is often incomplete or chronic, commonly due to infection. Many molecules involved in repair bind to heparin/heparan sulfate. The syndecan family of transmembrane proteoglycans is the major source of cell surface heparan sulfate, and serves as receptors or co-receptors for a variety of ligands. The syndecan extracellular domains (ectodomains) are shed from cell surfaces via receptor activation by agents involved in wound repair; shedding instantly changes syndecan function from cell surface receptor or co-receptor to soluble effector. Syndecan expression is highly regulated during skin wound repair. Syndecan-1 is lost from migratory keratinocytes, but induced in dermal capillaries, syndecan-4 is induced in dermal fibroblasts, and syndecan-1 and - ectodomains are shed into wound fluid where they regulate growth factor and proteolytic balance. Syndecan-1 null and syndecan-1 over- expression mice both show impaired skin wound repair, but by distinct mechanisms. These data lead to an overall hypothesis that syndecans coordinate, in part, the reparative response to tissue injury. Study of this hitherto unrecognized role provides new approaches to pathogenesis that should uncover novel preventive and/or therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028735-18
Application #
6172442
Study Section
Pathobiochemistry Study Section (PBC)
Program Officer
Mohla, Suresh
Project Start
1980-06-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
18
Fiscal Year
2000
Total Cost
$425,260
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Long, Olivia S; Gosai, Sager J; Kwak, Joon Hyeok et al. (2011) Using Caenorhabditis elegans to study serpinopathies. Methods Enzymol 499:259-81
Reizes, Ofer; Goldberger, Olga; Smith, April C et al. (2006) Insulin promotes shedding of syndecan ectodomains from 3T3-L1 adipocytes: a proposed mechanism for stabilization of extracellular lipoprotein lipase. Biochemistry 45:5703-11
Gotte, Martin; Bernfield, Merton; Joussen, Antonia M (2005) Increased leukocyte-endothelial interactions in syndecan-1-deficient mice involve heparan sulfate-dependent and -independent steps. Curr Eye Res 30:417-22
Wang, Zihua; Gotte, Martin; Bernfield, Merton et al. (2005) Constitutive and accelerated shedding of murine syndecan-1 is mediated by cleavage of its core protein at a specific juxtamembrane site. Biochemistry 44:12355-61
Elenius, Varpu; Gotte, Martin; Reizes, Ofer et al. (2004) Inhibition by the soluble syndecan-1 ectodomains delays wound repair in mice overexpressing syndecan-1. J Biol Chem 279:41928-35
Gotte, Martin (2003) Syndecans in inflammation. FASEB J 17:575-91
Gotte, Martin; Joussen, Antonia M; Klein, Christoph et al. (2002) Role of syndecan-1 in leukocyte-endothelial interactions in the ocular vasculature. Invest Ophthalmol Vis Sci 43:1135-41
Park, P W; Pier, G B; Preston, M J et al. (2000) Syndecan-1 shedding is enhanced by LasA, a secreted virulence factor of Pseudomonas aeruginosa. J Biol Chem 275:3057-64
Fitzgerald, M L; Wang, Z; Park, P W et al. (2000) Shedding of syndecan-1 and -4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase. J Cell Biol 148:811-24
Park, P W; Reizes, O; Bernfield, M (2000) Cell surface heparan sulfate proteoglycans: selective regulators of ligand-receptor encounters. J Biol Chem 275:29923-6

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