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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063825-03
Application #
6725383
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2004
Total Cost
$247,332
Indirect Cost
Name
Northwestern University at Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Tandara, Andrea A; Mustoe, Thomas A (2011) MMP- and TIMP-secretion by human cutaneous keratinocytes and fibroblasts--impact of coculture and hydration. J Plast Reconstr Aesthet Surg 64:108-16
Gallant-Behm, Corrie L; Mustoe, Thomas A (2010) Occlusion regulates epidermal cytokine production and inhibits scar formation. Wound Repair Regen 18:235-44
Brown, Richard J; Lee, Michael J; Sisco, Mark et al. (2008) High-dose ultraviolet light exposure reduces scar hypertrophy in a rabbit ear model. Plast Reconstr Surg 121:1165-72
Kloeters, Oliver; Schierle, Clark; Tandara, Andrea et al. (2008) The use of a semiocclusive dressing reduces epidermal inflammatory cytokine expression and mitigates dermal proliferation and inflammation in a rat incisional model. Wound Repair Regen 16:568-75
Tandara, Andrea A; Mustoe, Thomas A (2008) The role of the epidermis in the control of scarring: evidence for mechanism of action for silicone gel. J Plast Reconstr Aesthet Surg 61:1219-25
Liu, W Robert; Lu, Leonard; Rosenberg, David S et al. (2007) Synergistic activation of extracellular signal-regulated kinase in human dermal fibroblasts by human telomerase reverse transcriptase and transforming growth factor-beta1. J Surg Res 143:415-21
Sisco, Mark; Liu, W Robert; Kryger, Zol B et al. (2007) Reduced up-regulation of cytoprotective genes in rat cutaneous tissue during the second cycle of ischemia-reperfusion. Wound Repair Regen 15:203-12
Kryger, Zol B; Sisco, Mark; Roy, Nakshatra K et al. (2007) Temporal expression of the transforming growth factor-Beta pathway in the rabbit ear model of wound healing and scarring. J Am Coll Surg 205:78-88
Reid, Russell R; Roy, Nakshatra; Mogford, Jon E et al. (2007) Reduction of hypertrophic scar via retroviral delivery of a dominant negative TGF-beta receptor II. J Plast Reconstr Aesthet Surg 60:64-72;discussion 73-4
Mogford, Jon E; Liu, W Robert; Reid, Russell et al. (2006) Adenoviral human telomerase reverse transcriptase dramatically improves ischemic wound healing without detrimental immune response in an aged rabbit model. Hum Gene Ther 17:651-60

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