Role of dermal extracellular matrix microenvironment in skin aging

摘要 这项拨款申请的主要目标是验证老年人基质金属蛋白酶-1（MMP 1）升高的假设 皮肤成纤维细胞引发真皮细胞外基质（ECM）的断裂，这反过来促进衰老过程 和年龄相关的皮肤病。这项拨款是为了响应国家老龄化研究所的资助机会而写的 公告PA-13-155（衰老研究动物模型的开发和表征）。 衰老影响所有人，是许多常见疾病的关键风险因素。老化皮肤的主要变化是 局限于真皮结缔组织，表现为薄而脆弱的皮肤。我们发现，MMP 1，它启动 胶原原纤维（其构成皮肤的主体以提供强度和弹性）的降解显著地 在老年人皮肤中增加。这种碎片化产生了异常的真皮ECM微环境，其破坏了真皮细胞的生长。 皮肤的结构完整性，并通过中断细胞-ECM相互作用而损害细胞功能。我们假设 胶原ECM微环境的改变驱动与年龄相关的皮肤病理，例如脆性增加， 受损的脉管系统支持、不良的伤口愈合和皮肤癌。 基于上述人体皮肤在体数据，我们最近产生了诱导型转基因小鼠（col-MMP 1），其 在皮肤成纤维细胞中特异性表达MMP 1，这是老年人皮肤中MMP 1升高的来源。col-MMP 1小鼠 表现出显著加速的皮肤老化，例如变薄、脆性增加、皱纹和碎片化。 真皮胶原纤维。这些特征与在老年人皮肤中观察到的特征非常相似。重要的是，col-MMP 1小鼠 显示出对皮肤癌/乳头状瘤发展的易感性显著增加，支持了异常的 真皮ECM微环境促进年龄相关的皮肤癌。 基于这些发现，我们推测，老年真皮成纤维细胞中MMP 1的升高改变了真皮ECM 微环境，这反过来又驱动衰老过程，并介导与年龄相关的皮肤病的发病机制。这 一项提案将通过1）确定ECM年龄相关改变的分子机制来验证上述假设。 微环境损害真皮成纤维细胞功能; 2）研究直接增强机械 刺激细胞功能的力，从而改善与年龄相关的ECM真皮微环境;以及3）确定 与年龄相关的真皮ECM微环境在紫外线照射引起的角质形成细胞癌发展中的作用， 化学致癌物这一建议具有创新性，可能会对老龄化和与年龄有关的领域产生深远的影响。 通过鉴定与年龄相关的ECM微环境作为治疗干预的关键靶点来治疗疾病。

ABSTRACT The major goal of this grant application is to test the hypothesis that elevated matrix metalloproteinase-1 (MMP1) in aged skin fibroblasts initiates fragmentation of dermal extracellular matrix (ECM), which in turn promotes the aging process and age-related skin pathologies. This grant is written in response to National Institute on Aging Funding Opportunity Announcement PA-13-155 (Development and Characterization of Animal Models for Aging Research). Aging affects all individuals, and is a key risk factor for many common diseases. The major alterations in aged skin are localized in the dermal connective tissue, manifested by thin, fragile skin. We found that MMP1, which initiates degradation of collagen fibrils, which comprise the bulk of skin to provide strength and resiliency, is significantly increased in aged human skin. This fragmentation creates an aberrant dermal ECM microenvironment, which disrupts the structural integrity of the skin and impairs cellular functions by interrupting cell-ECM interactions. We hypothesize that alteration of the collagenous ECM microenvironment drive age-related skin pathologies, such as increased fragility, impaired vasculature support, poor wound healing, and skin cancer. Based on above human skin in vivo data, we recently generated an inducible transgenic mouse (col-MMP1), which specifically expresses MMP1 in skin fibroblasts, the source of elevated MMP1 in aged human skin. col-MMP1 mice exhibit significantly accelerated skin aging, exemplified by thinning, increased fragility, wrinkling, and fragmented dermal collagen fibrils. These features closely mimic those observed in aged human skin. Importantly, col-MMP1 mice show substantially increased susceptibility to skin cancer/papilloma development, supporting the concept that aberrant dermal ECM microenvironment promotes age-related skin cancer. Based on these findings, we hypothesize that elevated MMP1 in aged dermal fibroblast alters dermal ECM microenvironment, which in turn drives the aging process and mediates the pathogenesis of age-related skin diseases. This proposal will test above hypothesis, by 1): determining molecular mechanisms by which age-related alteration of ECM microenvironment impairs dermal fibroblast functions; 2) investigating the ability of direct enhancement of mechanical force to stimulate cell function and thereby improve age-related ECM dermal microenvironment; and 3) Determine the role of age-related dermal ECM microenvironment on keratinocyte cancer development caused by UV irradiation and chemical carcinogens. This proposal is innovative and may have profound impact on the field of aging and age-related diseases by identifying age-related ECM microenvironment as a key target for therapeutic intervention.