The main objective of this proposal is to improve our understanding of the molecular biology and gene regulation involved in the mechanisms of tissue contraction by studying (1) the differential alteration of mesenchymal cells and the extracellular matrix by different TGF-beta isoforms, (2) the pattern of TGF-beta isoform gene expression in response to exogenous TGF-beta1, 2, and 3, (3) the selective pattern of TGF-beta isoform gene expression using a subtractive hybridization technique. The cellular and molecular mechanisms underlying tissue contraction are poorly understood. Recently, we have developed a fetal wound healing model whereby we are able to induce excisional wounds, which would otherwise expand, to contract and close in response to the sustained delivery of the various isoforms of TGF-beta. TGF-beta1 induced contraction that was accompanied by an increase in inflammation, fibrosis, and procollagen gene expression. TGF-beta3 also induced contraction, however without concomitant increase in inflammation, fibrosis, or procollagen gene expression. This model of inducing contraction without inflammation provides a unique and effective model to study tissue contraction. The proposed studies will analyze the mechanisms of open wound contraction and the role of TGF- beta. Understanding the underlying gene regulation involved in wound contraction would provide a significant advancement in developing biochemical therapies that will treat conditions with inadequate (i.e. diabetic ulcers) or excessive tissue contraction (i.e. pulmonary fibrosis or cirrhosis).
