Abstract

This is a competitive renewal application from Dr. Welgus to investigate various aspects of the control of collagenase and matrix- metalloproteinase (MMP) production by human keratinocytes in culture.
The specific aims are to: 1) define matrix components which induce collagenase production by cultured keratinocytes, identify the cell surface recognition integrins that mediate the induction, and study the signal transduction pathways; 2) define the mechanism of matrix-induced collagenase expression, by identifying cis-acting promoter elements in the collagenase 5' flanking region of the gene, and identify trans acting factors that bind to these sequences and modulate gene expression; 3) determine the factors and gene regulatory mechanisms controlling the expression of stromelysin-1 and stromelysin-2, which are apparently expressed in vivo in wound repair by distinctly different populations of keratinocytes; and 4) study collagenase and stromelysin-1 and -2 expression in a skin-equivalent model of keratinocyte cultures after wounding.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR035805-11
Application #
2079103
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1984-12-01
Project End
1999-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
11
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Barnes-Jewish Hospital
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63110

  Publications

Wang, M; Qin, X; Mudgett, J S et al. (1999) Matrix metalloproteinase deficiencies affect contact hypersensitivity: stromelysin-1 deficiency prevents the response and gelatinase B deficiency prolongs the response. Proc Natl Acad Sci U S A 96:6885-9
Pilcher, B K; Gaither-Ganim, J; Parks, W C et al. (1997) Cell type-specific inhibition of keratinocyte collagenase-1 expression by basic fibroblast growth factor and keratinocyte growth factor. A common receptor pathway. J Biol Chem 272:18147-54
Dunsmore, S E; Rubin, J S; Kovacs, S O et al. (1996) Mechanisms of hepatocyte growth factor stimulation of keratinocyte metalloproteinase production. J Biol Chem 271:24576-82
Garlick, J A; Parks, W C; Welgus, H G et al. (1996) Re-epithelialization of human oral keratinocytes in vitro. J Dent Res 75:912-8
Brown-Augsburger, P; Hartshorn, K; Chang, D et al. (1996) Site-directed mutagenesis of Cys-15 and Cys-20 of pulmonary surfactant protein D. Expression of a trimeric protein with altered anti-viral properties. J Biol Chem 271:13724-30
Sires, U I; Dublet, B; Aubert-Foucher, E et al. (1995) Degradation of the COL1 domain of type XIV collagen by 92-kDa gelatinase. J Biol Chem 270:1062-7
Pentland, A P; Shapiro, S D; Welgus, H G (1995) Agonist-induced expression of tissue inhibitor of metalloproteinases and metalloproteinases by human macrophages is regulated by endogenous prostaglandin E2 synthesis. J Invest Dermatol 104:52-7
Sires, U I; Schmid, T M; Fliszar, C J et al. (1995) Complete degradation of type X collagen requires the combined action of interstitial collagenase and osteoclast-derived cathepsin-B. J Clin Invest 95:2089-95
Busiek, D F; Baragi, V; Nehring, L C et al. (1995) Matrilysin expression by human mononuclear phagocytes and its regulation by cytokines and hormones. J Immunol 154:6484-91
Cornelius, L A; Nehring, L C; Roby, J D et al. (1995) Human dermal microvascular endothelial cells produce matrix metalloproteinases in response to angiogenic factors and migration. J Invest Dermatol 105:170-6

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