Human skin, like all other organs, undergoes alterations as a consequence of aging. Reduced function of aged skin is largely caused by irreversible destruction of fibrillar collagen, the major structural protein in skin connective tissue (dermis). As the US population ages, morbidity from loss of collagen decline of skin connective tissue function is becoming an increasing public health concern. The long-term objective of this grant application is to understand molecular mechanisms that are responsible for degradation of fibrillar collagen during aging, and thereby develop preventative and therapeutic remedies to improve the health of aged human skin. We have found that matrix metalloproteinase-1 (MMP-1), the enzyme responsible for initiating cleavage of fibrillar collagen is significantly elevated in aged (>80 years old), compared to young (18-29 years old) human skin dermal fibroblasts in vivo. Overproduction of MMP-1 by dermal fibroblasts causes fragmentation and disorganization of collagen fibrils. This loss of structural integrity of collagen fibrils is a critical factor in the age-related functional impairment of human skin connective tissue. The specific focus of this grant application is to investigate molecular mechanisms that cause this age-dependent MMP-1 overexpression in human skin connective tissue. Based on our preliminary data obtained by direct measurements of young and aged human skin, we hypothesize that elevated MMP-1 levels in aged connective tissue results from the interdependent actions of four MMP-1 regulators: 1) transcription factor AP-1, 2) alpha2beta1 integrin, 3) transforming growth factor-beta1, and 4) reactive oxygen species. These four factors are coordinately regulated through mechanical tension exerted on dermal fibroblasts by its physical interactions with the collagenous extracellular matrix of skin connective tissue, in which they reside. MMP-1-mediated collagen fibril fragmentation results in weakened mechanical tension within dermal fibroblasts. This weakened mechanical tension promotes further expression of MMP-1, and thereby sets in motion a positive feedback pathway of skin connective tissue destruction.
Our specific aims are designed to test this working model, using two experimental approaches;1) direct measurements of relevant transcripts, proteins, and enzyme activities in small samples of human skin from individuals of different age groups, and 2) molecular analysis of MMP-1 regulation in a three dimensional collagen lattice fibroblast culture model, which recapitulates the salient features of MMP-1 overexpression observed in aged human skin connective tissue in vivo. By using these two experimental approaches in a systematic integrated manner, we will investigate the aging process directly in human's largest organ, skin. Given that connective tissue biology is similar throughout the body, our results will likely be directly applicable to many organ systems, including lung, bone, joints, and heart. In addition to testing our hypothesis regarding the mechanism of age-dependent regulation of MMP-1, our proposed studies will provide direct quantitative measures that address the question of """"""""when does aging begin?"""""""", as it pertains to human skin connective tissue.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Aging Systems and Geriatrics Study Section (ASG)
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Williams, John
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Fisher, Gary J; Shao, Yuan; He, Tianyuan et al. (2016) Reduction of fibroblast size/mechanical force down-regulates TGF-? type II receptor: implications for human skin aging. Aging Cell 15:67-76
Quan, Taihao; Fisher, Gary J (2015) Role of Age-Associated Alterations of the Dermal Extracellular Matrix Microenvironment in Human Skin Aging: A Mini-Review. Gerontology 61:427-34
Quan, Taihao; Johnston, Andrew; Gudjonsson, Johann E et al. (2015) CYR61/CCN1: A Novel Mediator of Epidermal Hyperplasia and Inflammation in Psoriasis? J Invest Dermatol 135:2562-2564
Xia, Wei; Quan, Taihao; Hammerberg, Craig et al. (2015) A mouse model of skin aging: fragmentation of dermal collagen fibrils and reduced fibroblast spreading due to expression of human matrix metalloproteinase-1. J Dermatol Sci 78:79-82
Wang, Frank; Smith, Noah R; Tran, Bao Anh Patrick et al. (2014) Dermal damage promoted by repeated low-level UV-A1 exposure despite tanning response in human skin. JAMA Dermatol 150:401-6
Qin, Zhaoping; Voorhees, John J; Fisher, Gary J et al. (2014) Age-associated reduction of cellular spreading/mechanical force up-regulates matrix metalloproteinase-1 expression and collagen fibril fragmentation via c-Jun/AP-1 in human dermal fibroblasts. Aging Cell 13:1028-37
Quan, Taihao; Little, Emily; Quan, Hehui et al. (2013) Elevated matrix metalloproteinases and collagen fragmentation in photodamaged human skin: impact of altered extracellular matrix microenvironment on dermal fibroblast function. J Invest Dermatol 133:1362-6
Xia, Wei; Hammerberg, Craig; Li, Yong et al. (2013) Expression of catalytically active matrix metalloproteinase-1 in dermal fibroblasts induces collagen fragmentation and functional alterations that resemble aged human skin. Aging Cell 12:661-71
Qin, Zhaoping; Fisher, Gary J; Quan, Taihao (2013) Cysteine-rich protein 61 (CCN1) domain-specific stimulation of matrix metalloproteinase-1 expression through ?V?3 integrin in human skin fibroblasts. J Biol Chem 288:12386-94
Fang, Ming; Goldstein, Elizabeth L; Turner, A Simon et al. (2012) Type I collagen D-spacing in fibril bundles of dermis, tendon, and bone: bridging between nano- and micro-level tissue hierarchy. ACS Nano 6:9503-14

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