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：
9176369
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/9176369
关键词：
Address Affect Age Aging Aging-Related Process American Animal Model Applications Grants Cancer Etiology Cell Shape Cell physiology Cells Characteristics Chronic Collagen Collagen Fibril Connective Tissue Data Dermal Dermis Development Disease Elasticity Epithelial Exhibits Exposure to Extracellular Matrix Fibroblasts Funding Opportunities Goals Grant Homeostasis Human Individual Interstitial Collagenase Life Malignant Neoplasms Mechanics Mediating Molecular Mus National Cancer Institute National Institute on Aging Papilloma Pathogenesis Pathology Predisposition Public Health Research Risk Factors Role Skin Skin Aging Skin Cancer Source Structural Genes Testing Therapeutic Intervention Transgenic Mice Wound Healing Writing age related aged base cancer type chemical carcinogen improved in vivo innovation keratinocyte mouse model novel response skin disorder targeted treatment ultraviolet irradiation

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.

抽象的本次拨款申请的主要目标是检验老年人基质金属蛋白酶 1 (MMP1) 升高的假设皮肤成纤维细胞启动真皮细胞外基质（ECM）的破碎，进而促进衰老过程和与年龄相关的皮肤病变。这笔赠款是为了响应国家老龄化研究所的资助机会而写的公告 PA-13-155（衰老研究动物模型的开发和表征）。衰老影响所有人，并且是许多常见疾病的关键危险因素。老化皮肤的主要变化是位于真皮结缔组织，表现为皮肤薄而脆弱。我们发现MMP1，它启动胶原纤维（构成皮肤的大部分以提供强度和弹性）的降解显着老年人皮肤中增加。这种碎片会产生异常的真皮 ECM 微环境，从而破坏破坏皮肤的结构完整性，并通过中断细胞与 ECM 的相互作用来损害细胞功能。我们假设胶原 ECM 微环境的改变会导致与年龄相关的皮肤病变，例如脆性增加、血管支持受损、伤口愈合不良和皮肤癌。基于上述人体皮肤体内数据，我们最近制备了一种可诱导的转基因小鼠（col-MMP1），特异性在皮肤成纤维细胞中表达 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，例如变薄、脆弱、皱纹和破碎真皮胶原纤维。这些特征与在老年人类皮肤中观察到的特征非常相似。重要的是，col-MMP1 小鼠显示对皮肤癌/乳头状瘤发展的易感性显着增加，支持异常的概念真皮 ECM 微环境促进与年龄相关的皮肤癌。基于这些发现，我们假设衰老真皮成纤维细胞中 MMP1 升高会改变真皮 ECM 微环境，进而驱动衰老过程并介导与年龄相关的皮肤病的发病机制。这该提案将通过 1) 来检验上述假设：确定 ECM 与年龄相关的改变的分子机制微环境损害真皮成纤维细胞功能； 2）考察直接增强机械性能的能力力刺激细胞功能，从而改善与年龄相关的ECM真皮微环境； 3) 确定年龄相关的真皮 ECM 微环境对紫外线照射引起的角质形成细胞癌发展的作用化学致癌物。该提案具有创新性，可能对老龄化及年龄相关领域产生深远影响通过将与年龄相关的 ECM 微环境确定为治疗干预的关键目标来治疗疾病。