Role of dermal extracellular matrix microenvironment in skin aging

摘要 这项拨款申请的主要目的是检验这样一种假设，即老年人中升高的基质金属蛋白酶-1(MMP1) 皮肤成纤维细胞启动真皮细胞外基质(ECM)的碎裂，进而促进衰老过程 以及与年龄相关的皮肤病变。这笔赠款是对国家老龄基金机会研究所的回应 公告PA-13-155(衰老研究动物模型的发展和表征)。 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。我们发现了MMP1，它启动了 胶原蛋白纤维的降解是显著的，胶原纤维是皮肤的主要组成部分，提供力量和弹性。 在老化的人类皮肤中增加。这种碎片化造成了一个异常的真皮ECM微环境，从而破坏了 皮肤的结构完整性，并通过中断细胞与细胞外基质的相互作用而损害细胞功能。我们假设 胶原细胞外基质微环境的改变会导致与年龄相关的皮肤病变，如脆性增加， 血管支持受损，伤口愈合不良，以及皮肤癌。 基于上述人体皮肤活体数据，我们最近获得了一种可诱导的转基因小鼠(ol-MMP1)，该小鼠 MMP1在皮肤成纤维细胞中特异表达，这是老年人皮肤中MMP1升高的来源。COL-MMP1小鼠 显著加速皮肤老化，表现为皮肤变薄、脆弱、皱纹和碎裂 真皮胶原纤维。这些特征与在老化的人类皮肤上观察到的特征非常相似。重要的是，ol-Mmp1小鼠 显示对皮肤癌/乳头状瘤发展的易感性显著增加，支持这种异常的概念 真皮细胞外基质微环境促进年龄相关性皮肤癌。 基于这些发现，我们假设老年真皮成纤维细胞中MMP1的升高改变了真皮细胞外基质。 微环境，它反过来驱动衰老过程，并介导与年龄相关的皮肤病的发病机制。这 提案将通过1)：确定与年龄相关的ECM改变的分子机制来检验上述假设 微环境对真皮成纤维细胞功能的损害；2)研究机械直接增强的能力 刺激细胞功能从而改善与年龄相关的ECM真皮微环境的力量；以及3)确定 增龄相关真皮细胞外基质微环境在紫外线照射致角质形成细胞癌发生中的作用 化学致癌物。这一建议具有创新性，可能会对老龄化和老龄相关领域产生深远影响 通过确定与年龄相关的ECM微环境作为治疗干预的关键目标，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.