Fibroblast Differentiation in Wound Healing

University Of Oklahoma Hlth Sciences Ctr, Oklahoma City OK

Investigators

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Abstract

DESCRIPTION (provided by applicant): Wound healing defects can result from lack of fibroblast migration as observed in non-healing chronic wounds or from excessive myofibroblast formation and function as observed in scarring and pathological contractures. Our long term goal is to regulate fibroblast migration, myofibroblast formation and function, and scarring during abnormal wound healing and to manipulate these cells for therapeutic purposes. The objective is to determine how expression of cytoskeletal proteins in fibroblasts and myofibroblasts are transcriptionally regulated and the consequences altering transcriptional activity has on their formation and function during wound healing. Our central hypothesis is that myocardin-related transcription factor (MRTF)-A and -B are key regulators of fibroblasts and myofibroblasts during wound healing. The significance is that by understanding MRTF regulation of fibroblasts and myofibroblasts, transcriptional activity of MRTFs can be manipulated, resulting in innovative approaches to preventing and treating chronic wounds, scarring and contractures. To test our hypothesis we will pursue the following specific aims: 1) Identify the transcriptional regulation o contractile protein expression essential for myofibroblast formation and function during wound healing. We hypothesize that MRTF-A is essential for myofibroblast formation, contraction, wound closure, and scar formation. We will evaluate MRTF-A regulation of myofibroblast formation and scarring in wound healing and scarring using MRTF-A- null mice and in in vitro models of wound healing. 2) Determine how fibroblast migration is transcriptionally regulated during wound healing. We hypothesize that MRTF-A and -B redundantly control fibroblast migration essential for granulation tissue formation. MRTF-A and -B regulation of fibroblast migration will be evaluated during wound healing using MRTF-A/B-null mice. The transcriptional activity of MRTF-A and -B in human chronic wound fibroblasts will be evaluated, in vivo and in vitro, and whether increasing transcriptional activity of MRTF-A and -B can restore fibroblast migration. 3) Identify the functional differences between MRTF-A and -B transcriptional activity during wound healing. We hypothesize that MRTF-A and -B have redundant transcriptional activity for fibroblast migration and differing transcriptional activity for myofibroblast formatio during wound healing. Using a MRTF inhibitor, we will determine whether differential MRTF transcriptional activity can maintain fibroblast migration and inhibit myofibroblast formation and scarring. We will evaluate the different cytoskeletal proteins expressed in response to MRTF-A and -B and the mechanisms for these differing transcriptional activities. This is significant because it is a first step in therapeutically regulating fibroblasts and myofibroblasts during wound healing through regulation of specific transcription factors. This is innovative because it focuses on an entirely different approach to controlling fibroblast migration, myofibroblast formation and scarring by altering transcriptional activity of key transcription factors and provides a novel approach to in the treatment of non-healing wounds, scarring, and pathologic contractures.