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

真皮ECM微环境对皮肤衰老和癌症的影响

• 批准号: 10637690
• 负责人: GARY J FISHER
• 金额: $ 65.48万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637690
• 关键词: Acceleration; Affect; Age Months; Aging; Applications Grants; Cell Aging; Cells; Characteristics; Clinical; Collagen; Collagen Fibril; Collagen Type I; Contusions; Cutaneous; Data; Dermal; Dermis; Deterioration; Development; Disease; Elasticity; Elements; Enzymes; Exhibits; Extracellular Matrix; Family; Fibroblasts; Goals; Homeostasis; Human; Immunity; Impairment; Individual; Inflammaging; Inflammation Mediators; Inflammatory; Interstitial Collagenase; Knowledge; Malignant Neoplasms; Matrix Metalloproteinases; Mediator; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Papilloma; Pathogenesis; Pathology; Pathway interactions; Play; Predisposition; Process; Production; Protein Secretion; Risk Factors; Signal Transduction; Skin; Skin Aging; Skin Cancer; Source; Stromal Cells; Structural Protein; Structure; Testing; Therapeutic Intervention; Thinness; Transforming Growth Factor beta; Transgenes; age related; aged; cancer initiation; cytokine; human data; human model; humanized mouse; in vivo; inflammatory milieu; innovation; keratinocyte; mechanical force; mechanical properties; member; mouse model; novel; skin disorder; targeted treatment; tumor; wound healing

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.

摘要 这项拨款申请的主要目标是确定与年龄相关的 真皮成纤维细胞中基质金属蛋白酶-1（MMP-1）的升高创造了一个微环境， 衰老过程和与年龄有关的皮肤病，包括癌症。 衰老影响所有人，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真皮变薄、皱纹、下垂和失去弹性， 这是由于皮肤中的主要结构蛋白质胶原蛋白的破坏和降解引起的。恶化 真皮胶原纤维也与年龄相关的皮肤病直接相关，如撕裂，瘀伤，皮肤老化和皮肤老化。 伤口愈合，并严重有助于削弱免疫力和癌症。我们发现这个矩阵 启动胶原纤维裂解的金属蛋白酶-1（MMP 1）在老年人中显著增加， 人皮肤真皮成纤维细胞。这种增加与胶原蛋白的破碎和解体有关 纤维化并在真皮（真皮）中产生与年龄相关的异常细胞外基质（ECM）微环境 老化）。 基于上述人体皮肤体内数据，我们最近通过以下方法产生了皮肤真皮老化的小鼠模型： 人MMP-1的成纤维细胞特异性表达是老年人皮肤中MMP-1升高的来源， 通过基质细胞特异性pdgfra-Cre转基因（pdgfra-Cre; MMP 1）。pdgfra-Cre; MMP 1小鼠表现出 显著加速皮肤老化，这与在老化的人类皮肤中观察到的非常相似。重要的是， pdgfra-Cre; MMP 1小鼠对皮肤癌/乳头状瘤发展的易感性显著增加， 提示皮肤老化微环境促进年龄相关的角质形成细胞皮肤癌。 基于这些发现，我们假设皮肤成纤维细胞中MMP 1的年龄相关性升高导致了 皮肤ECM的渐进性改变，其产生促进皮肤老化的微环境 过程和年龄相关的皮肤病，包括癌症。这个数据驱动的假设是基于一本小说 皮肤真皮老化是由成纤维细胞对周围细胞外环境的适应所控制的概念 基质（ECM）微环境（由外向内适应），而不是细胞自主因素。我们提出 根据具体目标来检验上述假设。目的1：确定分子特征/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 以非细胞内在方式适应周围ECM微环境。目标3：定义 皮肤微环境老化对角化细胞癌发生的影响。这项建议是 创新，并可能通过识别年龄，对老龄化和与年龄有关的疾病领域产生深远的影响， 相关ECM微环境作为治疗干预的关键目标。