The impact of the dermal ECM microenvironment on cutaneous aging and cancer

摘要 这项资助申请的主要目标是确定与年龄相关的分子机制 真皮成纤维细胞中基质金属蛋白酶-1(MMP1)的升高创造了一个促进 衰老过程和与年龄相关的皮肤病理，包括癌症。 老龄化影响所有人，是包括癌症在内的大多数常见疾病的最大风险因素。 老年人皮肤的特征包括皮肤变薄、皱纹、松弛和失去弹性， 这是由于皮肤中的主要结构蛋白--胶原蛋白的破坏和降解造成的。劣化 真皮胶原蛋白fiBrins也与年龄相关的皮肤疾病直接相关，如撕裂、瘀伤、不良 伤口愈合，并严重导致免疫力减弱和癌症。我们找到了那个矩阵 随着年龄的增长，启动胶原纤维裂解的金属蛋白酶-1(MMP1)显著增加 人皮肤真皮成纤维细胞。这种增加与胶原的碎裂和解体有关。 在真皮(真皮)形成纤维并创造与年龄相关的异常细胞外基质(ECM)微环境 老化)。 基于上述人体皮肤活体数据，我们最近通过以下方法建立了皮肤皮肤老化的小鼠模型 人MMP1的成纤维细胞特异性表达驱动，MMP1是老年人皮肤中升高的MMP1的来源 通过基质细胞特异性的PDGFRA-Cre转基因(PDGFRA-Cre；MMP1)。PDGFRA-Cre；MMP1小鼠表现出 显著加速皮肤衰老，这与在老化的人类皮肤上观察到的情况非常相似。重要的是 小鼠对皮肤癌/乳头状瘤的易感性显著增加， 提示皮肤老化微环境促进年龄相关性角质形成细胞皮肤癌的发生。 基于这些发现，我们假设与年龄相关的真皮成纤维细胞中MMP1的升高导致 皮肤细胞外基质的渐进性改变，这创造了一个促进皮肤衰老的微环境 过程和年龄相关的皮肤病理，包括癌症。这一数据驱动的假说是基于一种新的 皮肤皮肤衰老是由成纤维细胞对周围细胞外环境的适应决定的 基质(ECM)微环境(由外向内适应)，而不是细胞自主因素。我们建议 以下是对上述假设进行检验的具体目的。目标1：确定分子签名/途径 在皮肤老化过程中。目的2：研究成纤维细胞驱动皮肤衰老的机制 以非细胞固有的方式适应周围的细胞外基质微环境。目标3：定义 真皮微环境老化对角质形成细胞癌发生的影响。这项建议是 通过识别年龄，创新并可能对老龄化和与年龄相关的疾病领域产生深远影响 相关的ECM微环境作为治疗干预的关键靶点。

ABSTRACT The major goal of this grant application is to determine the molecular mechanisms by which age-related elevation of matrix metalloproteinase-1 (MMP1) in dermal fibroblasts creates a microenvironment that promotes the aging process and age-related skin pathologies, including cancer. Aging affects all individuals and is the single greatest risk factor for most common diseases, including cancer. The characteristic features of aged human skin include dermal thinning, wrinkles, sagging and loss of elasticity, resulting from disruption and degradation of collagen, the major structural protein in skin. Deterioration of dermal collagen fibrils is also directly connected to age‐related skin morbidities, such as tearing, bruising, poor wound healing, and critically contributes to weakened immunity, and cancer. We found that matrix metalloproteinase-1 (MMP1), which initiates cleavage of collagen fibrils, is significantly increased in aged human skin dermal fibroblasts. This increase is associated with fragmentation and disorganization of collagen fibrils and creates age-related aberrant extracellular matrix (ECM) microenvironment in the dermis (dermal aging). Based on above human skin in vivo data, we have recently generated a mouse model of skin dermal aging by fibroblast-specific expression of human MMP1, the source of the elevated MMP-1 in aged human skin, driven by a stromal cell-specific pdgfra-Cre transgene (pdgfra-Cre;MMP1). pdgfra-Cre;MMP1 mice exhibit significantly accelerated dermal aging, which closely mimics those observed in aged human skin. Importantly, pdgfra-Cre;MMP1 mice have substantially increased susceptibility to skin cancer/papilloma development, suggesting dermal aging microenvironment promotes age-related keratinocyte skin cancer. Based on these findings, we hypothesize that age-related elevation of MMP1 in dermal fibroblasts leads to progressive alterations of the dermal ECM, which creates a microenvironment that promotes the dermal aging process and age-related skin pathologies, including cancer. This data-driven hypothesis is based on a novel concept that skin dermal aging is governed by the adaptation of fibroblasts to the surrounding extracellular matrix (ECM) microenvironment (outside-in adaptation), rather than cell‐autonomous factors. We propose following Specific Aims to test above hypothesis. Aim 1: Determine the Molecular Signatures/Pathways During Dermal Aging Process. Aim 2: Investigate Mechanisms by which Dermal Aging is Driven by Fibroblast Adaptation to the Surrounding ECM Microenvironment in a Non-Cell-Intrinsic Manner. Aim 3: Define the Impact of Ageing of the Dermal Microenvironment on Keratinocyte Cancer Initiation. 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.