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

• 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
• 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

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.

摘要