Age-associated changes in integrin function during cutaneous wound healing

描述（由申请人提供）：表皮功能的改变在老化皮肤中发生的伤口愈合并发症的发病机制中至关重要。更好地了解老化皮肤中角质细胞与皮肤细胞外基质的相互作用是如何改变的，对于理解伤口愈合中年龄相关缺陷的机制至关重要。整合素a3b1是层粘连蛋白332的细胞外基质受体，在表皮基底细胞层表达，在伤口愈合过程中上调。我们实验室之前的研究表明，a3b1是角化细胞迁移和伤口再上皮化的关键调节因子。此外，我们最近的数据表明，a3b1在诱导角化细胞中促血管生成因子的表达方面具有独特而全新的作用，因此它可能介导表皮和内皮细胞之间的串导，从而促进伤口血管生成。这些发现表明，表皮中a3b1的表达对于皮肤伤口愈合的两个不同且基本的方面很重要，即上皮再生和血管生成，这两个方面在老化的皮肤中都减少了，可能导致老年人伤口愈合受损。因此，a3b1是介导表皮伤口愈合功能的极好候选者，这种功能随着年龄的增长而减弱，它为旨在改善老年人伤口愈合的治疗方法提供了可能的靶点。在我们提出的研究中，我们将把衰老皮肤的小鼠模型与表皮特异性a3敲除相结合，以测试表皮中a3b1表达的减少是否会使皮肤容易出现伤口愈合缺陷，并测试表皮中促进伤口愈合的特异性a3b1功能是否在衰老皮肤中发生改变。为了表征所涉及的分子机制，这些体内方法将通过细胞培养研究来补充，以确定角化细胞中随年龄变化的a3b1依赖功能。这项工作将有助于我们了解整合素介导的表皮对ECM的反应如何在内在衰老过程中发生变化，以及这些变化是否有助于老化皮肤伤口愈合的减少，并可能为老年患者伤口治疗提供新的治疗靶点。公共卫生相关性：开发促进老年人皮肤伤口愈合的治疗方法的关键是确定控制伤口修复的分子机制，并了解这些机制如何在老化的皮肤中发生变化。这些研究将确定表皮整合素在伤口愈合过程中调节角质形成细胞迁移和血管生成中的新作用，并将探索这些功能的年龄相关变化是否会导致皮肤老化时伤口愈合受损。这些通路可作为促进老年患者伤口修复的治疗靶点。

DESCRIPTION (provided by applicant): Changes in epidermal function are critically important in the pathogenesis of wound healing complications that occur in ageing skin. A better understanding of how keratinocyte interactions with the cutaneous extracellular matrix are altered in ageing skin is essential to understanding mechanisms that underlie age-related defects in wound healing. Integrin a3b1 is an extracellular matrix receptor for laminin-332 that is expressed in the basal cell layer of the epidermis and is upregulated during wound healing. Previous studies from our lab have shown that a3b1 is a critical regulator of keratinocyte migration and wound reepithelialization. In addition, our recent data suggest a distinct and completely novel role for a3b1 in inducing expression of pro-angiogenic factors in keratinocytes, whereby it may mediate cross-talk between the epidermis and endothelial cells that promotes wound angiogenesis. These findings suggest that a3b1 expression in epidermis is important for two distinct and fundamental aspects of cutaneous wound healing, reepithelialization and angiogenesis, both of which are reduced in ageing skin and may contribute to impaired wound healing in the elderly. Therefore, a3b1 is an excellent candidate for mediating epidermal wound healing functions that diminish with age, and it provides a likely target for therapeutic approaches aimed at improving wound healing in the elderly. In the proposed research, we will combine a murine model of ageing skin with epidermis-specific a3 knockout to test if reduced a3b1 expression in the epidermis predisposes skin to wound healing defects, and to test if specific a3b1 functions in the epidermis that facilitate wound healing are altered in aged skin. In order to characterize the molecular mechanisms involved, these in vivo approaches will be complemented by cell culture studies to identify a3b1-dependent functions in keratinocytes that change as a function of age. This work should enhance our understanding of how integrin-mediated epidermal responses to ECM change during intrinsic ageing and whether these changes contribute to reduced wound healing in aged skin, and it may reveal new therapeutic targets for wound treatment in elderly patients. PUBLIC HEALTH RELEVANCE: A key to the development of therapies to facilitate cutaneous wound healing in the elderly is the identification of molecular mechanisms that control wound repair, and an understanding of how those mechanisms change in aging skin. The proposed studies will identify novel roles for integrins of the epidermis in regulating keratinocyte migration and angiogenesis during wound healing, and will explore whether age-related changes in these functions contribute to impaired wound healing in aging skin. These pathways may be exploitable as therapeutic targets to facilitate wound repair in elderly patients.