Human skin, like all other organs, undergoes alterations as a consequence of the passage of time. In aged human skin, the dermal connective tissue architecture undergoes progressive degradation, which impairs skin function and causes skin to become thin and fragile. Aged skin bruises easily. Wound healing is slow and incomplete, further weakening the skin. Skin fragility largely results from irreversible deterioration of the structure and organization of fibrillar collagen, the most abundant structural protein in skin. The long-term goal of the parent proposal and this supplemental revision is to delineate mechanisms that are responsible for structural and functional deterioration of collagen fibrils that occur during human skin aging. Based on our preliminary data, we hypothesize that skin aging begins at a relatively young age brought about by gradual accumulation of partially degraded collagen, which results from matrix metalloproteinase-1 (MMP-1)-catalyzed collagen cleavage. This collagen breakdown alters interactions between the dermal extracellular matrix and fibroblasts, which produce, organize and directly contact the extracellular matrix. The impact of broken collagen is to reduce dynamic mechanical tension exerted between fibroblasts and the extracellular matrix. Reduced mechanical tension alters fibroblast function;inducing MMP-1 expression and lowering collagen production, thereby causing further deterioration of skin connective tissue. To directly test this hypothesis, we have generated transgenic mice that constitutively express high levels of MMP-1 in skin. In support of our hypothesis, skin connective tissue in these mice undergoes rapid deterioration, which resembles that observed in aged human skin. This supplemental revision application proposes to utilize this newly created mouse model of skin connective aging to investigate molecular mechanisms by which MMP-1-mediated collagen fragmentation alters fibroblast function during the aging process.
The long-term goal of the parent proposal and this supplemental revision is to delineate mechanisms that are responsible for structural and functional deterioration of skin connective tissue, which occurs during human skin aging. This age-related degradation of skin causes skin to become thin and fragile. Aged skin bruises easily and heals poorly. As the United States population ages, the deleterious impact of aging on skin function is a rising, significant health concern.
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