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.
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