Age-associated changes in integrin function during cutaneous wound healing

描述（由申请方提供）：表皮功能的变化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。更好地了解角质形成细胞与皮肤细胞外基质的相互作用如何在老化皮肤中改变，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a3 b1是层粘连蛋白-332的细胞外基质受体，其在表皮的基底细胞层中表达并且在伤口愈合期间上调。我们实验室以前的研究表明，a3 b1是角质形成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，一个独特的和全新的作用a3 b1在诱导角质形成细胞中的促血管生成因子的表达，从而它可能介导表皮和内皮细胞之间的串扰，促进伤口血管生成。这些研究结果表明，a3 b1在表皮中的表达是重要的皮肤伤口愈合，上皮再生和血管生成，这两个不同的和基本的方面是减少在老化的皮肤，并可能有助于受损的伤口愈合在老年人。因此，a3 b1是介导随着年龄增长而减少的表皮伤口愈合功能的优秀候选者，并且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。在拟议的研究中，我们将联合收割机与表皮特异性a3基因敲除的老化皮肤的小鼠模型相结合，以测试表皮中a3 b1表达的减少是否使皮肤易于伤口愈合缺陷，并测试表皮中促进伤口愈合的特定a3 b1功能是否在老化皮肤中改变。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，以确定角质形成细胞中随年龄变化的a3 b1依赖性功能。这项工作应提高我们的理解，整合素介导的表皮细胞外基质的变化，在内在老化过程中，这些变化是否有助于减少伤口愈合的老年皮肤，它可能会揭示新的治疗目标，为伤口治疗老年患者。公共卫生相关性：开发促进老年人皮肤伤口愈合的疗法的关键是确定控制伤口修复的分子机制，并了解这些机制在老化皮肤中如何变化。拟议的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的新作用，并将探讨这些功能中与年龄相关的变化是否有助于衰老皮肤中伤口愈合受损。这些途径可作为治疗靶点，以促进老年患者的伤口修复。

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.