Following the completion of his Internal Medicine and Rheumatology Training, the candidate joined the laboratory of Dr. Sergio A Jimenez who has had a long-standing interest in the extracellular matrix and mechanism of excessive connective tissue deposition in fibrotic diseases. Work by the Candidate demonstrated that Transforming Growth Factor-is a potent stimulator of connective tissue production. The mechanisms responsible are poorly understood; elevated mRNA levels account, at least partially, for these effects.
The aim of the present proposal is to elucidate the level of stimulation of collagen and fibronectin gene expression by TGF-. In these studies, the effects of TGF- on the rates of in vitro, collagen mRNA synthesis and degradation will be examined. Employing transient transection experiments with a eukaryotic shuttle Vector, collagen gene regulating sequences will be introduced onto normal fibroblasts in order to identify regions responsible for TGF- activation of collagen gene transcription. The induction of DNA-binding proteins by TGF will be determined using DNAse protection and gel retardation experiments. The candidate was recently appointed Assistant Professor at Thomas Jefferson University in the Division of Research Rheumatology, headed by his sponsor, who has a joint appointment with the Jefferson Institute of Molecular Medicine. The institute, directed by Dr. Darwin Prockop consist of over 30,000 square feet of newly renovated laboratory space, and a research faculty with considerable experience in various aspects of connective tissue research. Drs. Jimenez and Uitto (Co-sponsor) are investigators with established collaboration who have expertise in examining fibrotic diseases utilizing state of the art techniques of molecular biology, and have agreed to meet with this with this Candidate on a regular basis to provide guidance and supervision in carrying out the proposed project. Other faculty members with expertise relevant to the proposed research are readily available for consultation. A large number of human sequence specific cDNAs probes corresponding to Types I, III and VI collagens, fibronectin and laminin as well as institute and will be made available for these studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AR001817-04
Application #
3079280
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Project Start
1989-01-01
Project End
1993-12-31
Budget Start
1992-01-01
Budget End
1992-12-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Kane, G C; Varga, J; Conant, E F et al. (1996) Lung involvement in systemic sclerosis (scleroderma): relation to classification based on extent of skin involvement or autoantibody status. Respir Med 90:223-30
Varga, J; Yufit, T; Hitraya, E et al. (1996) Control of extracellular matrix degradation by interferon-gamma. The tryptophan connection. Adv Exp Med Biol 398:143-8
Yufit, T; Vining, V; Wang, L et al. (1995) Inhibition of type I collagen mRNA expression independent of tryptophan depletion in interferon-gamma-treated human dermal fibroblasts. J Invest Dermatol 105:388-93
Varga, J; Yufit, T; Brown, R R (1995) Inhibition of collagenase and stromelysin gene expression by interferon-gamma in human dermal fibroblasts is mediated in part via induction of tryptophan degradation. J Clin Invest 96:475-81
Rudnicka, L; Varga, J; Christiano, A M et al. (1994) Elevated expression of type VII collagen in the skin of patients with systemic sclerosis. Regulation by transforming growth factor-beta. J Clin Invest 93:1709-15
Varga, J; Li, L; Mauviel, A et al. (1994) L-Tryptophan in supraphysiologic concentrations stimulates collagenase gene expression in human skin fibroblasts. Lab Invest 70:183-91
Varga, J; Heiman-Patterson, T; Munoz, S et al. (1993) Myopathy with mitochondrial alterations in patients with primary biliary cirrhosis and antimitochondrial antibodies. Arthritis Rheum 36:1468-75
Varga, J; Jimenez, S A; Uitto, J (1993) L-tryptophan and the eosinophilia-myalgia syndrome: current understanding of the etiology and pathogenesis. J Invest Dermatol 100:97S-105S
Clements, P J; Lachenbruch, P A; Seibold, J R et al. (1993) Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 20:1892-6
Varga, J; Li, L; Jimenez, S A (1993) Increased type I collagen gene expression in L-tryptophan associated eosinophilia-myalgia syndrome skin fibroblasts. J Rheumatol 20:1303-8

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