Role of TGF-b In Excessive Scarring: A Cutaneous Model

皮肤损伤部位的过度或增生性疤痕通常会产生功能和审美缺陷，从而严重影响个人在社会中的功能。我们的长期目标是发展诊断和治疗方法，促进皮肤伤口的正常解决，而不会形成过多的疤痕。我们的初步工作集中在证明兔增生性瘢痕模型与人类状况的临床相关性。该模型以多种方式模拟人类状况，包括对类固醇和闭塞治疗的反应性以及随着年龄增长而减少的肥大。最重要的是，我们的模型和人类的肥大是由于细胞外基质，主要是胶原蛋白的过量产生。在损伤过程中，对胶原合成最有效的调节因子是tgf - β细胞因子家族。我们的中心假设是TGFbeta调节伤口愈合和瘢痕形成的方式，其三种同种异构体的优势及其丰度和外观的时间序列决定了伤口愈合反应的瘢痕结果。此外，我们假设tgf β受体（I和11）和tgf β细胞内信号元件的Smad成员在维持肥厚状态中发挥关键作用。这些假设将使用我们临床相关的兔子增生性瘢痕模型进行检验。我们的具体目标是：(1)利用我们独特的兔耳增生性瘢痕模型，支持tgf - β亚型出现的比例和时间模式及其对胶原合成的总体影响对增生性瘢痕与正常瘢痕的发展至关重要的假设。(2)利用基因治疗方法，在过表达I型和II型受体，并用显性阴性受体阻断它们的过程中，tgf β受体的表达在时间上、绝对数量和比例上的改变在肥厚性疤痕的发展中很重要。这种改变受体在体内表达的新方法将被研究其潜在的治疗意义。(3)通过改变SMAD 3、4、7表达的病毒和非病毒基因治疗方法改变tgf β信号转导，并测量对tgf β异构体表达、增生性瘢痕的发展和胶原1表达的影响，进一步验证tgf β异构体表达对增生性瘢痕发展至关重要的假设。

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.