The broad, long-term objectives of this proposal are to understand the molecular mechanisms that are responsible for loss of type I procollagen synthesis in chronologically aged and photoaged human skin. Type I collagen is the major structural protein in human skin and provides skin with strength and resiliency. Type I collagen is synthesized in a precursor form, type I procollagen, by fibroblasts that reside in skin connective tissue. As skin ages, as a consequence of either the passage of time, or chronic exposure to ultraviolet (UV) irradiation from the sun (photoaging), type I procollagen synthesis declines. This loss of type I procollagen is a major contributing factor to thinning and increased fragility of naturally aged skin, and the old wrinkled appearance of photoaged skin. The mechanism responsible for loss of type I procollagen production in naturally aged and photoaged human skin is not known. The major regulator of type I procollagen synthesis is the transforming growth factor-beta (TGF-B)ISmad pathway. Evidence indicates that TGF-B regulates procollagen production both directly and indirectly, via TGF-B-regulated connective tissue growth factor (CTGF). UV irradiation impairs the TGF-B/Smad pathway, and this impairment is associated with reduced CTGF expression and reduced type I procollagen synthesis in human skin in vivo and human skin fibroblasts in vitro. Inhibition of the TGF-13/Smad pathway by UV irradiation occurs primarily as a consequence of down-regulation of the TGF-B receptor type II. This proposal will test the hypothesis that the TGF-B/Smad pathway is impaired in naturally aged and photoaged human skin, and that this impairment contributes to loss of type I procollagen synthesis.
The specific aims are: 1) characterize TGF-13/SMAD signaling pathway in chronologically aged versus young human skin in vivo, 2) characterize TGF-B/SMAD signaling pathway in photoaged versus non-photoaged human skin in vivo, 3) determine the mechanisms by which UV inhibits TGF-B type II receptor gene expression in human skin fibroblasts, and 4) determine the role of CTGF in reduced procollagen in aged and photoaged human skin and the mechanism by which CTGF regulates procollagen production in human skin fibroblasts. The information obtained from the proposed studies will provide important new insights into modalities for treatment and prevention of age-related loss of skin strength and resiliency.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG019364-03
Application #
6696929
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Carrington, Jill L
Project Start
2002-02-01
Project End
2007-01-31
Budget Start
2004-03-01
Budget End
2005-01-31
Support Year
3
Fiscal Year
2004
Total Cost
$302,000
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dermatology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Quan, Chunji; Yan, Yan; Qin, Zhaoping et al. (2018) Ezrin regulates skin fibroblast size/mechanical properties and YAP-dependent proliferation. J Cell Commun Signal 12:549-560
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
Shao, Y; He, T; Fisher, G J et al. (2017) Molecular basis of retinol anti-ageing properties in naturally aged human skin in vivo. Int J Cosmet Sci 39:56-65
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
Argyropoulos, Angela J; Robichaud, Patrick; Balimunkwe, Rebecca Mutesi et al. (2016) Alterations of Dermal Connective Tissue Collagen in Diabetes: Molecular Basis of Aged-Appearing Skin. PLoS One 11:e0153806
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
Fisher, Gary J (2015) Cancer resistance, high molecular weight hyaluronic acid, and longevity. J Cell Commun Signal 9:91-2
RittiƩ, Laure; Fisher, Gary J (2015) Natural and sun-induced aging of human skin. Cold Spring Harb Perspect Med 5:a015370
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

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