Role of TGF-b In Excessive Scarring: A Cutaneous Model

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Excessive, or hypertrophic, scarring at sites of cutaneous injury often produces functional and aesthetic deficits that can strongly impact the function of an individual in society. Our long-term goal is to develop diagnostic and therapeutic treatments that promote normal resolution of cutaneous wounds without excessive scar formation. Our preliminary work has focused on demonstrating the clinical relevance of a rabbit model of hypertrophic scarring to the human condition. This model mimics the human condition in a variety of ways including responsiveness to steroid and occlusive treatments and a reduced hypertrophy with aging. Most importantly, the hypertrophy of our model and humans is due to excessive production of extracellular matrix, primarily collagen. The most powerful regulator of collagen synthesis during wounding is the TGFbeta family of cytokines. Our central hypothesis is that TGFbeta regulates wound healing and scarring in a manner that the preponderance of its three isoforms and the temporal sequence of their abundance and appearance determine the scarring outcome of a wound healing response. Furthermore, we hypothesize that the TGFbeta receptors (I and 11) and the Smad members of the TGFbeta intracellular signalling components play critical roles in the maintenance of the hypertrophic state. These hypotheses will be tested using our clinically relevant rabbit hypertrophic scarring model. Our Specific Aims are: (1) To support the hypothesis that the ratio and temporal pattern of the appearance of TGFbeta isoforms and their overall impact on collagen synthesis is critical to the importance of the development of hypertrophic scar vs. normal scar utilizing our unique hypertrophic scar model in the rabbit ear. (2) To examine the hypothesis that alterations in the expression of TGFbeta receptors temporally, in absolute numbers, and ratios are important in the development of hypertrophic scar utilizing a gene therapy approach, both overexpressing Type I and Type II receptors, and blocking them with dominant negative receptors. This novel approach of modifying receptor expression in vivo will be examined for its potential therapeutic implications. (3) To further examine the hypothesis that TGFbeta isoform expression is critical to the development of hypertrophic scar by altering TGFbeta signal transduction through viral and non-viral gene therapy approaches of altering expression of SMAD 3,4,7, and measuring the impact on TGFbeta isoform expression, development of hypertrophic scar, and collagen 1 expression.