Response to Burn Injury: Role of the Melanocortin System in Wound Repair

描述(由申请人提供)：增生性瘢痕(HTS)的形成通常发生在愈合的深部真皮伤口，包括烧伤、擦伤和皮肤移植供区，发生率接近60%。美国烧伤协会估计，在美国，每年有超过50万人的烧伤需要治疗。尽管有重要的临床见解，但对增生性瘢痕的病理生理学缺乏了解阻碍了治疗的进展。一项临床观察表明，皮肤色素沉着的患者增生性瘢痕形成的风险增加，黑素皮质素1受体(MC1R)调节人类皮肤的色素沉着，还发挥其他靶细胞反应，包括抗炎、解热和免疫调节。MC1R基因编码区是高度多态的，单核苷酸多态(SNPs)影响大约30%的普通人群。我们提出了一个新的假设，即调节色素沉着的基因的单核苷酸多态改变了对皮肤损伤的炎症和纤维增殖反应，并导致增生性瘢痕的形成。我们将通过两个目标来解决这个问题：1)黑素皮质素系统中基因的多态性与临床增生性瘢痕相关。我们将招募1000名烧伤患者参加IRB批准的试验，并将增生性瘢痕形成与与色素沉着相关的基因中的SNPs相关联。我们使用候选基因扫描，主要关注黑素皮质素信号通路中的基因，以分析一次性血液样本中DNA的多态。我们将与华盛顿大学临床基因组学中心合作，利用他们在基因分型和人群基因组学方面的专业知识。2.)MC1R调节成纤维细胞对损伤的反应，包括纤维增殖反应、迁移和增殖。我们将确定MC1R功能丧失和功能获得对成纤维细胞成纤维细胞增殖反应的影响，包括增殖、迁移、分化和蛋白质合成。 公共卫生相关性：我们提出了一个新的假设，即与色素沉着相关的基因的自然发生突变会改变皮肤损伤的炎症和纤维增殖性反应，并使患者更容易形成增生性瘢痕。我们将招募1000名烧伤患者，并将与色素沉着相关的基因突变与疤痕形成的临床评估相关联。我们还将确定黑素皮质素1受体功能丧失和功能获得对成纤维细胞反应的影响，包括增殖、迁移、分化和蛋白质合成。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.