There is now considerable evidence that both cellular and non-cellular components of the dermis exert significant influence on epidermal cell differentiation, epidermal-dermal adhesion, and normal development of skin basement membrane. Furthermore, aberrations within the dermis and/or basement membrane may lead to the clinical findings associated with several blistering diseases of the skin; most notably epidermolysis bullosa (EB). Within the past few years artificial dermal biomatrices have been produced and successfully used as substrates for growth and at least partial differentiation of epidermal cells; further technological improvements in this field undoubtedly will have great impact on the future treatment of burns and ulcerative diseases of the skin. In addition, such reconstituted skin may be potentially used to establish long awaited models for diseases such as EB. Unfortunately, to date the dermal biomatrices which have been produced lack close biochemical similarity to normal intact dermis, thereby potentially limiting their long term usefulness as artificial skin or as models of particular disease states. The first objective of this study is to develop a biochemically and physiologically more natural dermal biomatrix by reconstitution of human fibroblasts with purified native human matrix constituents (collagen types I, III, V, and VI; fibronectin; dermal proteoglycans) found in intact human dermis. Second, several purified basement membrane components will be added to the biomatrix surface prior to the addition of epidermal cells, so as to assess the functional roles and influences of such constituents on the reconstituted skin. Third, recombinant skin equivalents will be prepared using the optimized dermal biomatrix and cells from patients with EB. These latter recombinants will then be evaluated in vitro by immunological, biochemical, and morphological means and in vivo as xenographs in order to critically assess the influence of fibroblasts, epidermal cells, and extracellular matrix constituents in each of the forms of EB and ultimately establish a realistic laboratory model for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR036629-03
Application #
3157698
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1985-09-30
Project End
1989-08-31
Budget Start
1987-09-01
Budget End
1989-08-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Horiguchi, Y; Fine, J D; Couchman, J R (1991) Human skin basement membrane-associated heparan sulphate proteoglycan: distinctive differences in ultrastructural localization as a function of developmental age. Br J Dermatol 124:410-4
Vaidya, S; Tyring, S K; Johnson, L B et al. (1991) HLA and epidermolysis bullosa. Association between the HLA complex and recessive dystrophic epidermolysis bullosa. Arch Dermatol 127:1524-7
Vaidya, S; Tyring, S K; Feldkamp, M et al. (1991) HLA and epidermolysis bullosa: evidence for independent assortment of Weber-Cockayne subtype of epidermolysis bullosa and HLA complex. J Dermatol Sci 2:155-60
Fine, J D; Horiguchi, Y; Stein, D H et al. (1990) Intraepidermal type VII collagen. Evidence for abnormal intracytoplasmic processing of a major basement membrane protein in rare patients with dominant and possibly localized recessive forms of dystrophic epidermolysis bullosa. J Am Acad Dermatol 22:188-95
Fine, J D; Holbrook, K A; Elias, S et al. (1990) Applicability of 19-DEJ-1 monoclonal antibody for the prenatal diagnosis or exclusion of junctional epidermolysis bullosa. Prenat Diagn 10:219-29
Fine, J D; Horiguchi, Y; Jester, J et al. (1989) Detection and partial characterization of a midlamina lucida-hemidesmosome-associated antigen (19-DEJ-1) present within human skin. J Invest Dermatol 92:825-30
Fine, J D; Couchman, J R (1989) Chondroitin 6-sulfate proteoglycan but not heparan sulfate proteoglycan is abnormally expressed in skin basement membrane from patients with dominant and recessive dystrophic epidermolysis bullosa. J Invest Dermatol 92:611-6
Horiguchi, Y; Couchman, J R; Ljubimov, A V et al. (1989) Distribution, ultrastructural localization, and ontogeny of the core protein of a heparan sulfate proteoglycan in human skin and other basement membranes. J Histochem Cytochem 37:961-70
Fine, J D; Tyring, S; Gammon, W R (1989) The presence of intra-lamina lucida blister formation in epidermolysis bullosa acquisita: possible role of leukocytes. J Invest Dermatol 92:27-32
Fine, J D; Horiguchi, Y; Couchman, J R (1989) 19-DEJ-1, a hemidesmosome-anchoring filament complex-associated monoclonal antibody. Definition of a new skin basement membrane antigenic defect in junctional and dystrophic epidermolysis bullosa. Arch Dermatol 125:520-3

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