Hypertrophic scar (HTS) formation regularly occurs in healed, deep dermal wounds including burns, abrasions, and skin graft donor sites approaching 60% incidence. The American Burn Association estimates that over 500,000 burns injuries require medical treatment annually in the United States. In spite of important clinical insights, poor understanding of the pathophysiology of hypertrophic scar has hindered therapeutic advances. One clinical observation is that patients with pigmented skin have increased risk for hypertrophic scar formation, Melanocortin 1 receptor (MC1R) regulates human cutaneous pigmentation and also exerts other target cell responses, including anti-inflammatory, anti-pyretic, and immunoregulation. The coding region of the MC1R gene is highly polymorphic and single nucleotide polymorphisms (SNPs) affect approximately 30% of the general population. We propose the novel hypothesis that single nucleotide polymorphisms in genes that regulate pigmentation alter inflammatory and fibroproliferative responses to cutaneous injury and lead to hypertrophic scar formation. We will address this with two aims: 1) Polymorphisms in genes in the melanocortin system correlate with clinical hypertrophic scarring. We will enroll 1000 burn patients into an IRB approved trial and correlate hypertrophic scar formation with SNPs in genes associated with pigmentation. We use a candidate gene scan with primary focus on genes in the melanocortin signaling pathway to analyze polymorphisms in DNA from a one-time blood sample. We will collaborate with the UW Center for Clinical Genomics to take advantage of their expertise in genotyping and population genomics. 2.) MC1R regulates fibroblast responses to injury including fibroproliferative responses, migration and proliferation. We will determine the effect of MC1R loss-of-function and gain-of-function on fibroblast fibroproliferative responses including proliferation, migration, differentiation, and protein synthesis.
We propose the novel hypothesis that naturally occurring mutations in genes related to pigmentation alter inflammatory and fibroproliferative responses to cutaneous injury and predispose patients to hypertrophic scar formation. We will enroll 1000 burn patients and correlate mutations in genes related to pigmentation with clinical assessments of scar formation. We will also determine the effect of loss of function and gain of function for the melanocortin 1 receptor on fibroblast responses including proliferation, migration, differentiation, and protein synthesis.
|Seaton, Max E; Parent, Brodie A; Sood, Ravi F et al. (2017) Melanocortin-1 Receptor Polymorphisms and the Risk of Complicated Sepsis After Trauma: A Candidate Gene Association Study. Shock 47:79-85|
|Sood, Ravi F; Arbabi, Saman; Honari, Shari et al. (2016) Missense Variant in MAPK Inactivator PTPN5 Is Associated with Decreased Severity of Post-Burn Hypertrophic Scarring. PLoS One 11:e0149206|
|Sood, Ravi F; Hocking, Anne M; Muffley, Lara A et al. (2015) Genome-wide Association Study of Postburn Scarring Identifies a Novel Protective Variant. Ann Surg 262:563-9|
|Sirimahachaiyakul, Pornthep; Sood, Ravi F; Muffley, Lara A et al. (2015) Race Does Not Predict Melanocyte Heterogeneous Responses to Dermal Fibroblast-Derived Mediators. PLoS One 10:e0139135|
|Sood, Ravi F; Hocking, Anne M; Muffley, Lara A et al. (2015) Race and Melanocortin 1 Receptor Polymorphism R163Q Are Associated with Post-Burn Hypertrophic Scarring: A Prospective Cohort Study. J Invest Dermatol 135:2394-2401|
|Sood, Ravi F; Muffley, Lara A; Seaton, Max E et al. (2015) Dermal Fibroblasts from the Red Duroc Pig Have an Inherently Fibrogenic Phenotype: An In Vitro Model of Fibroproliferative Scarring. Plast Reconstr Surg 136:990-1000|
|Thompson, Callie M; Hocking, Anne M; Honari, Shari et al. (2013) Genetic risk factors for hypertrophic scar development. J Burn Care Res 34:477-82|
|Muffley, Lara A; Zhu, Kathy Q; Engrav, Loren H et al. (2011) Spatial and temporal localization of the melanocortin 1 receptor and its ligand ýý-melanocyte-stimulating hormone during cutaneous wound repair. J Histochem Cytochem 59:278-88|