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

对烧伤的反应：黑皮质素系统在伤口修复中的作用

基本信息

批准号：
7763766
负责人：
NICOLE SIMONE GIBRAN
金额：
$ 29.33万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-10 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7763766
关键词：
Address Adenylate Cyclase Affect Alleles American Anti-Inflammatory Agents Anti-inflammatory Asians Binding Blood specimen Burn injury Candidate Disease Gene Cell Nucleus Cells Characteristics Chronic Cicatrix Cleaved cell Clinical Clinical assessments Code Collagen Type I Contracts Cutaneous Cyclic AMP-Responsive DNA-Binding Protein DNA Data Dermal Disease Endorphins Endothelial Cells Enrollment Enzymes Esthetics Family suidae Fibroblasts Functional disorder G-Protein-Coupled Receptors General Population Genes Genetic Polymorphism Genetic Variation Genomics Genotype Hair Healed Hispanics Hormones Human Hypertrophic Cicatrix Impairment Incidence Individual Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Innovative Therapy Intercellular adhesion molecule 1 Lead Medical Melanocortin 1 Receptor Melanocyte stimulating hormone Metabolic Molecular Target Mutate Mutation Native Americans Neuropeptides Nitric Oxide Oxidative Stress Patients Peptides Phenotype Phosphorylation Pigmentation physiologic function Pigments Population Population Study Prevention Pro-Opiomelanocortin Production Protein Biosynthesis RNA Interference Receptor Activation Receptor Gene Rehabilitation therapy Research Ethics Committees Risk Role Scanning Signal Pathway Silicones Single Nucleotide Polymorphism Site Skin Skin Cancer Skin Carcinoma Skin Transplantation Skin graft Steroids Stigmata System Temperature Therapeutic Thick Time Transfection United States Variant Wound Healing alpha-Melanocyte stimulating hormone base eumelanin functional loss gain of function healing immunoregulation insight keratinocyte loss of function loss of function mutation macrophage melanocyte melanoma migration novel pheomelanin pressure protein function public health relevance receptor response response to injury social stigma

项目摘要

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.

描述（由申请人提供）：肥厚性疤痕（HTS）形成经常发生在愈合的深层皮肤伤口中，包括烧伤，擦伤和皮肤移植物供体部位接近60％的发病率。美国烧伤协会估计，在美国，每年有超过500,000次烧伤受伤需要医疗治疗。尽管有重要的临床见解，但对肥厚疤痕的病理生理学的理解不足，妨碍了治疗的进步。一种临床观察结果是，皮肤色素的患者具有增加肥厚性疤痕形成的风险，黑色素皮质素1受体（MC1R）调节人皮肤色素沉着，并发挥其他靶细胞反应，包括抗炎，抗染料和免疫调查。 MC1R基因的编码区是高度多态性的，单核苷酸多态性（SNP）影响了大约30％的一般人群。我们提出了一个新的假设，即调节色素沉着的基因中的单核苷酸多态性改变了对皮肤损伤的炎症和纤维增生性反应，并导致肥大性疤痕形成。我们将以两个目的解决这个问题：1）黑色素皮质系统中基因中的多态性与临床肥大疤痕相关。我们将招募1000名烧伤患者参加IRB认可的试验，并将肥厚性疤痕形成与与色素沉着相关的基因中的SNP相关。我们使用候选基因扫描，主要关注黑色皮质素信号传导途径中的基因，以分析一次性血液样本中DNA中的多态性。我们将与大学临床基因组学中心合作，利用它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，包括纤维增生反应，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纤维增生性反应的影响，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，即与色素化有关的基因自然发生突变改变了对皮肤损伤的炎症和纤维增生性反应，对皮肤损伤以及对肥厚性疤痕形成的患者倾向。我们将招募1000名烧伤患者，并将与色素沉着有关的基因与疤痕形成的临床评估相关。我们还将确定黑素皮质1受体的功能丧失和功能增益对成纤维细胞反应（包括增殖，迁移，分化和蛋白质合成）的影响。