Scleroderma is characterized by excessive accumulation of collagen and other matrix components in the skin and visceral organs. Fibroblasts isolated from the skin of patients with scleroderma synthesize increased amounts of collagen, a property that is propagable in vitro. We previously demonstrated that normal fibroblast are phenotypically heterogeneous in their metabolic activity. The hypothesis that clonal selection of normally occuring, high collagen synthesizing fibroblasts, is a pathogenetic mechanism in scleroderma will be used as a working model to examine the basis for abnormal metabolic activity in this disorder. Selective overgrowth of scleroderma fibroblasts may be mediated by products of immune cells, which infiltrate scleroderma skin, and/or growth factors and other mediators in the connective tissue environment. The infiltration of immune cells, and subsequent mediator release, may be mediated in part by specific adhesion ligands on lymphocytes and fibroblasts. We will determine whether scleroderma fibroblasts have abnormal sensitivity to immune cell derived cytokines and other mediators which regulate bodies in an attempt to distinguish, based on surface markers, among clonal fibroblast populations. In situ studies in scleroderma skin, monoclonal antibodies which distinguish among clonal fibroblast populations will be used constituent population, i.e. clonal restriction. These studies will be combined with analysis of collagen production by in situ hybridization. Similar studies will be performed with fibroblast populations cloned from scleroderma and normal skin. Finally, to examine a possible basis for immune cell localization in scleroderma skin, we will examine whether scleroderma lymphocytes and/or fibroblasts show increased adhesive properties and whether they express abnormal amounts of the adhesion ligands LFA-1 and ICAM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR032343-10
Application #
3156263
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1983-04-01
Project End
1993-09-30
Budget Start
1993-06-01
Budget End
1993-09-30
Support Year
10
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
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