Fibroblastic cells isolated from scleroderma skin and rheumatoid arthritis synovial tissue display abnormal metabolic phenotypes that play a role in disease pathogenesis. Furthermore, the metabolic alterations are persistent for many cell generations of in vitro culture. We propose to use in vitro models to investigate mechanisms whereby products of immune cells may lead to permanent phenotypic changes in connective tissue cell populations. We will utilize fibroblast substrains we have isolated which are heterogeneous in metabolic activity to study whether immune mediators might lead to preferential growth of certain subpopulations, i.e. clonal selection, and the possible mechanisms involved. The phenotypic distribution of fibroblast substrains isolated from scleroderma skin and rheumatoids synovium will be compared to that seen in normal controls. Synthesis of prostaglandin E2, collagen, collagenase and glycosaminoglycans, and message levels for alpha1(I), alpha2(I) and alpha1(III) collagen will be assayed as well as biosynthetic responses to interleukin-1, gamma interferon, and other mediators. Clonal distribution of collagen mRNA will also be examined by in situ hybridization. Finally, we will continue preliminary studies using monoclonal antibodies that may identify specific fibroblast subpopulations to study the clonal distribution of fibroblasts in in vitro experiments and in cells isolated from scleroderma skin and rheumatoid synovium.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR032343-04
Application #
3156255
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1983-04-01
Project End
1989-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
4
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
Jun, Jae-Bum; Kuechle, Melanie; Min, Junki et al. (2005) Scleroderma fibroblasts demonstrate enhanced activation of Akt (protein kinase B) in situ. J Invest Dermatol 124:298-303
Gardner, H; Strehlow, D; Bradley, L et al. (2004) Global expression analysis of the fibroblast transcriptional response to TGFbeta. Clin Exp Rheumatol 22:S47-57
Kissin, Eugene Y; Lemaire, Raphael; Korn, Joseph H et al. (2002) Transforming growth factor beta induces fibroblast fibrillin-1 matrix formation. Arthritis Rheum 46:3000-9
Widom, R L; Lee, J Y; Joseph, C et al. (2001) The hcKrox gene family regulates multiple extracellular matrix genes. Matrix Biol 20:451-62
Jelaska, A; Korn, J H (2000) Role of apoptosis and transforming growth factor beta1 in fibroblast selection and activation in systemic sclerosis. Arthritis Rheum 43:2230-9
Panchenko, M V; Farber, H W; Korn, J H (2000) Induction of heme oxygenase-1 by hypoxia and free radicals in human dermal fibroblasts. Am J Physiol Cell Physiol 278:C92-C101
Strehlow, D; Jelaska, A; Strehlow, K et al. (1999) A potential role for protease nexin 1 overexpression in the pathogenesis of scleroderma. J Clin Invest 103:1179-90
Jelaska, A; Strehlow, D; Korn, J H (1999) Fibroblast heterogeneity in physiological conditions and fibrotic disease. Springer Semin Immunopathol 21:385-95
Jelaska, A; Korn, J H (1998) Anti-Fas induces apoptosis and proliferation in human dermal fibroblasts: differences between foreskin and adult fibroblasts. J Cell Physiol 175:19-29
Gruber, B L; Kew, R R; Jelaska, A et al. (1997) Human mast cells activate fibroblasts: tryptase is a fibrogenic factor stimulating collagen messenger ribonucleic acid synthesis and fibroblast chemotaxis. J Immunol 158:2310-7

Showing the most recent 10 out of 33 publications