Role of dermal extracellular matrix microenvironment in skin aging

真皮细胞外基质微环境在皮肤衰老中的作用

基本信息

批准号：
9899818
负责人：
GARY J FISHER
金额：
$ 31.78万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899818
关键词：
Address Affect Age Aging American Animal Model Applications Grants Cell Shape Cell physiology Cells Characteristics Chronic Collagen Collagen Fibril Connective Tissue Data Dermal Dermis Development Disease Elasticity Epithelial Epithelium Exhibits Exposure to Extracellular Matrix Fibroblasts Funding Opportunities Goals Grant Homeostasis Human Impairment Individual Interruption Interstitial Collagenase Malignant Neoplasms Mediating Molecular Mus National Cancer Institute National Institute on Aging Papilloma Pathogenesis Pathology Predisposition Process Public Health Research Risk Factors Role Skin Skin Aging Skin Cancer Source Structural Protein Structure Testing Therapeutic Intervention Thinness Transgenic Mice age related aged base cancer type chemical carcinogen improved in vivo innovation keratinocyte mechanical force mouse model novel resilience response skin disorder targeted treatment ultraviolet irradiation wound healing

项目摘要

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.

抽象的该赠款应用的主要目的是检验以下假设：老年基质金属蛋白酶1（MMP1）升高皮肤成纤维细胞启动皮肤外基质（ECM）的碎片，从而促进衰老过程和与年龄有关的皮肤病理。这笔赠款是为了回应国家老化资金机会研究所而撰写的赠款公告PA-13-155（用于衰老研究的动物模型的开发和表征）。衰老会影响所有个人，并且是许多常见疾病的关键危险因素。老年皮肤的主要改变是位于皮肤结缔组织中，表现为薄而脆弱的皮肤。我们发现启动的MMP1 胶原蛋白原纤维的降解，包括大部分皮肤以提供强度和弹性，是显着的老年人皮肤增加。这种破碎产生了异常的皮肤ECM微环境，这破坏了皮肤的结构完整性和通过中断细胞ECM相互作用而损害细胞功能。我们假设这一点胶原性ECM微环境驱动与年龄相关的皮肤病理的改变，例如脆弱性增加，血管支撑损害，伤口愈合不良和皮肤癌。基于上述人体皮肤的体内数据，我们最近生成了可诱导的转基因小鼠（Col-MMP1），该小鼠特异性地表达了皮肤成纤维细胞中的MMP1，这是老年人皮肤中MMP1升高的来源。 Col-MMP1小鼠表现出明显加速的皮肤老化，以稀疏，脆弱性增加，皱纹和碎片为例真皮胶原蛋白原纤维。这些特征非常模仿那些在老年人皮肤中观察到的特征。重要的是，Col-MMP1小鼠显示出对皮肤癌/乳头状瘤发育的敏感性大大提高，支持了异常的概念皮肤ECM微环境促进与年龄有关的皮肤癌。基于这些发现，我们假设在老年皮肤成纤维细胞中升高的MMP1改变了皮肤ECM 微环境又驱动了衰老过程并介导了与年龄相关的皮肤疾病的发病机理。这提案将在上述假设上检验1）：确定与年龄相关的ECM改变的分子机制微环境会损害皮肤成纤维细胞功能； 2）研究机械的直接增强能力刺激细胞功能的力，从而改善与年龄相关的ECM真皮微环境； 3）确定与年龄相关的皮肤ECM微环境在紫外线照射和角色细胞癌发展中的作用化学致癌物。该提议具有创新性，可能会对衰老和与年龄有关的领域产生深远影响通过将与年龄相关的ECM微环境鉴定为治疗干预的关键目标，疾病。