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.

抽象的 该赠款应用的主要目标是确定与年龄相关的分子机制 皮肤成纤维细胞中基质金属蛋白酶-1（MMP1）的升高会产生一种微环境，可促进 衰老过程和与年龄有关的皮肤病理，包括癌症。 衰老会影响所有个体，并且是包括癌症在内的大多数常见疾病的最大危险因素。 老年人皮肤的特征包括皮肤稀疏，皱纹，下垂和弹性丧失， 胶原蛋白的破坏和降解，这是皮肤中主要的结构蛋白。恶化 皮肤胶原纤维也直接连接到与年龄相关的皮肤病性，例如撕裂，瘀伤，不良 伤口愈合，并严重导致免疫学和癌症减弱。我们发现矩阵 启动胶原纤维裂解的金属蛋白酶-1（MMP1）在老年人中显着增加 人皮肤皮肤成纤维细胞。这种增加与胶原蛋白的分裂和混乱有关 原纤维并创建与年龄相关的异常细胞外基质（ECM）微环境（真皮 老化）。 基于上述人体皮肤在体内数据中，我们最近通过 人类MMP1的成纤维细胞特异性表达，人类皮肤中升高的MMP-1的来源，驱动 通过基质细胞特异性PDGFRA-CRE转基因（PDGFRA-CRE; MMP1）。 PDGFRA-CRE; MMP1小鼠展示 显着加速了皮肤衰老，这些老化密切地模拟了在老年人皮肤中观察到的那些衰老。重要的是， PDGFRA-CRE; MMP1小鼠对皮肤癌/乳头状瘤发育的敏感性大大提高， 提示皮肤老化的微环境促进与年龄有关的角质形成细胞癌。 根据这些发现，我们假设皮肤成纤维细胞中与年龄相关的MMP1升高导致 皮肤ECM的渐进式改变，它创造了一种微环境，可促进皮肤衰老 过程和与年龄有关的皮肤病理，包括癌症。该数据驱动的假设基于新颖 皮肤皮肤衰老的概念是由成纤维细胞适应周围细胞外的 矩阵（ECM）微环境（外部适应），而不是细胞自动因素。我们建议 遵循以上假设检验的特定旨在测试。目标1：确定分子特征/途径 在真皮衰老过程中。 AIM 2：研究真皮衰老的机制由成纤维细胞驱动 以非细胞内在方式适应周围的ECM微环境。目标3：定义 皮肤微环境衰老对角质形成细胞癌启动的影响。该提议是 创新，可能会通过确定年龄 - 相关的ECM微环境是治疗干预的关键目标。