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.
The major goal of this application is to test the novel hypothesis that age-related increased fragmentation of collagen fibrils, due to elevation of matrix metalloproteinase-1 (MMP1), creates an aberrant dermal microenvironment that promotes the aging process and age-related skin pathologies. The proposed studies employ a novel mouse model of accelerated skin aging.
|Cole, Megan A; Quan, Taihao; Voorhees, John J et al. (2018) Extracellular matrix regulation of fibroblast function: redefining our perspective on skin aging. J Cell Commun Signal 12:35-43|
|Qin, Zhaoping; Fisher, Gary J; Voorhees, John J et al. (2018) Actin cytoskeleton assembly regulates collagen production via TGF-? type II receptor in human skin fibroblasts. J Cell Mol Med 22:4085-4096|
|Fisher, Gary; Rittié, Laure (2018) Restoration of the basement membrane after wounding: a hallmark of young human skin altered with aging. J Cell Commun Signal 12:401-411|
|Qin, Z; Balimunkwe, R M; Quan, T (2017) Age-related reduction of dermal fibroblast size upregulates multiple matrix metalloproteinases as observed in aged human skin in vivo. Br J Dermatol 177:1337-1348|