MOLECULAR MECHANISMS FOR KELOID FORMATION

瘢痕疙瘩形成的分子机制

• 批准号: 6375112
• 负责人: ERNST J REICHENBERGER
• 金额: $ 12.6万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-10 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6375112
• 关键词: clinical research; family genetics; fibroblasts; fibrosis; human genetic material tag; human subject; keloid skin disorder; linkage mapping; molecular pathology; tissue /cell culture; wound healing

The long-term goal of this study is to understand the molecular mechanisms of neoformation of dermal tissue in fibrotic diseases. To achieve this goal we began to study hereditary keloid formation. Keloids are benign tumors of the skin or cornea caused by clonal overactivity of fibroblasts during abnormal wound repair. The relatively large number of familial cases of keloid formation makes it possible to propose a genetic approach for the identification of a gene responsible for increased cell proliferation and extracellular matrix expression. We performed linkage analysis of one large family afflicted with an autosomal dominant form of hereditary keloid formation to identify the chromosomal locus of the disease gene by using polymorphic microsatellite markers covering the entire genome. We have identified a possible disease gene locus and are now in the process of establishing a high resolution map of the keloid locus by including other pedigrees that show locus homogeneity. Ideally, the interval will be restricted to less than 1-2 cM. The keloid gene will be identified by candidate gene cloning, positional candidate gene cloning, or positional cloning. We will construct a physical map of the keloid locus using YAC and cosmid clones covering this interval. Once the disease gene has been identified by mutation analysis and by co-segregation with the affected phenotype, studies are planned to characterize the protein product and its interactions with other genes or gene products. Depending on the nature of the keloid gene, we will plan in vitro studies of fibroblast and organ cultures as well as a mouse model that expresses the mutated gene by homologous recombination (knock-in). These studies should enable us to perform further studies on down-stream events, which are involved in the fibrosis of keloid scars. Identifying and characterizing the keloid gene product, and identifying other proteins or genes with which it interacts, will help us understand abnormal fibroblast regulation. We suggest that keloids are an excellent model for studying regulation of fibroblast activation and extracellular matrix expression during wound healing and fibrosis.

这项研究的长期目标是了解纤维化疾病中真皮组织新形成的分子机制。为了实现这一目标，我们开始研究遗传性循环形成。 酮是因缠绕在异常伤口修复过程中由成纤维细胞过度活动引起的皮肤或角膜的良性肿瘤。 相对较大的家族性乳突形成病例使得提出一种遗传方法，以鉴定负责增加细胞增殖和细胞外基质表达的基因。 我们对一个大型家庭进行了连锁分析，该家庭患有常染色体显性骨骼形式的遗传性乳突形成形式，通过使用覆盖整个基因组的多态性微卫星标记来鉴定疾病基因的染色体基因座。 我们已经确定了可能的疾病基因座，现在正在通过包括显示基因座均匀性的其他血统来建立高分辨率图。理想情况下，间隔将仅限于1-2厘米。酮基因将通过候选基因克隆，位置候选基因克隆或位置克隆来鉴定。 我们将使用覆盖此间隔的YAC和Cosmid克隆来构建酮基因座的物理图。 一旦通过突变分析鉴定出疾病基因并通过与受影响的表型共隔离来鉴定，计划的研究将表征蛋白质产物及其与其他基因或基因产物的相互作用。 根据乳突基因的性质，我们将计划对成纤维细胞和器官培养物的体外研究以及通过同源重组（敲入）表达突变基因的小鼠模型。 这些研究应使我们能够对下游事件进行进一步的研究，这些事件与乳子状疤痕的纤维化有关。 识别和表征酮基因产物，并鉴定与其相互作用的其他蛋白质或基因，将有助于我们了解异常的成纤维细胞调节。 我们认为，酮是研究在伤口愈合和纤维化过程中调节成纤维细胞激活和细胞外基质表达的绝佳模型。