The long-term objective of this research is to understand the pathogenesis of abnormal scar formation and, ultimately, to develop ways of preventing and treating these debilitating disorders. Hypertrophic scars and keloids result from abnormal accumulation of extracellular matrix; the underlying cause is not known. This revised competing continuation begins to address the hypothesis that aberrant scars arise as a consequence of functional heterogeneities intrinsic to dermal fibroblastic populations.
The specific aims are: (1) To determine if fibroblasts that are derived from normal skin, normal scar and hypertrophic/keloid scar are distinguishable from each other on the basis of glycosaminoglycan (GAG) synthesis and/or GAG synthesis in response to a biological response modifier (transforming growth factor- beta 1 [TGF-beta1]). (2) To determine if the """"""""GAG synthetic machinery: differs for fibroblasts derived from normal skin, normal scar and hypertrophic/keloid scar and whether it is affected by exposure to TGF- beta1. (3) To determine if the capacity for autocrine stimulation by TGF-beta1 differs between fibroblasts derived from normal and abnormal tissues and whether it provides an explanation for the increased accumulation of GAG in aberrant scarring. Mass cultures will be initiated for each of the tissue types. Using quantitative cellulose acetate electrophoresis and a panel of unique monoclonal antibodies that recognize novel epitopes in GAG chains, GAG content and composition will be measured both for cultures and for the native tissues from which they were initiated Comparisons will be made to confirm the existence of altered GAG synthetic phenotypes for normal versus abnormal scars and to verify that the altered phenotype persists in culture. Parallel cultures will be exposed and non-exposure to TgF-beta1 and the GAG determinations repeated. under conditions of exposure and non-exposure to TGF-beta 1, cultures expressing different GAG synthetic machineries. Finally, a possible autocrine possess the same or different GAG synthetic machineries. Finally, a possible autocrine mechanism of TGF-beta1- induced stimulation of GAG synthesis will be studies by comparing fibroblast cell lines with regard to their muRNA phenotypes for TGF- beta1. This will be done under conditions of exposure and non-exposure to exogenous TGF-beta1 to establish if expression of TGF-Beta1 muRNA differs according to (a) the normalcy of the tissue of origin and (b) history of exposure o exogenous TGF-beta1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE007803-06
Application #
3221579
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1989-02-01
Project End
1994-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
6
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Dentistry
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Bertolami, C N; Messadi, D V (1994) The role of proteoglycans in hard and soft tissue repair. Crit Rev Oral Biol Med 5:311-37
Bertolami, C N; Berg, S; Messadi, D V (1992) Binding and internalization of hyaluronate by human cutaneous fibroblasts. Matrix 12:11-21
Bertolami, C N; Bronson, R E (1990) Expression of different glycosaminoglycan synthetic phenotypes by lapine dermal and dermal wound fibroblasts. Matrix 10:1-9
Bronson, R E; Treat, J A; Bertolami, C N (1989) Fibroblastic subpopulations in uninjured and wounded rabbit oral mucosa. J Dent Res 68:51-8
Bronson, R E; Argenta, J G; Bertolami, C N (1988) Interleukin-1-induced changes in extracellular glycosaminoglycan composition of cutaneous scar-derived fibroblasts in culture. Coll Relat Res 8:199-208
Bertolami, C N; Ellis, D G; Donoff, R B (1988) Healing of cutaneous and mucosal wounds grafted with collagen-glycosaminoglycan/silastic bilayer membranes: a preliminary report. J Oral Maxillofac Surg 46:971-8
Bronson, R E; Argenta, J G; Siebert, E P et al. (1988) Distinctive fibroblastic subpopulations in skin and oral mucosa demonstrated by differences in glycosaminoglycan content. In Vitro Cell Dev Biol 24:1121-6
Ruggiero, S L; Bertolami, C N; Bronson, R E et al. (1987) Hyaluronidase activity of rabbit skin wound granulation tissue fibroblasts. J Dent Res 66:1283-7
Bronson, R E; Bertolami, C N; Siebert, E P (1987) Modulation of fibroblast growth and glycosaminoglycan synthesis by interleukin-1. Coll Relat Res 7:323-32