Regulation of Extracellular Matrix Homeostatsis in Skin Aging

Summary

Principal Investigator: Gary J Fisher
Affiliation: University of Michigan
Country: USA
Abstract: DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to understand molecular basis and functional impact of skin connective tissue aging. Skin, like all human organs, undergoes deleterious alterations as a consequence of the passage of time. Natural aging of skin is manifested primarily by thinning, largely due to loss of type I collagen in the dermis. Type I collagen is the most abundant protein in skin and confers structure, strength and resiliency. Age-dependent loss of collagen causes increased fragility and thereby makes skin more susceptible to bruising and impedes wound healing. Aging of the US population makes medical care of fragile skin a growing public health concern. In addition to being the largest human organ, skin is readily accessible for study. These unique properties of skin provide the opportunity study molecular mechanisms of aging in humans. The free radical theory of aging posits that natural aging is driven by cellular damage that results from oxidation by reactive oxygen species (ROS) that are generated as a consequence of aerobic metabolism. We find that ROS levels are elevated in aged human skin fibroblasts in vivo. Fibroblasts are the major cell type that produces type I collagen. In addition, we find that the TGF-2/SMAD/CTGF axis, which is the major regulatory network that drives type I collagen production in skin, is impaired in aged human skin. This impairment results from decreased expression of SMAD3, which is a downstream effector of TGF-2 actions, and reduced expression of connective tissue growth factor (CTGF), which is a multi-functional protein that acts in concert with TGF-2 to regulate type I collagen expression. Furthermore, we find that mild, short-term oxidative exposure of primary cultured human dermal fibroblasts causes permanent cellular alterations that closely mimic those observed in fibroblasts in aged skin in vivo;namely, increased ROS, reduced SMAD3, reduced CTGF, and reduced type I collagen expression. Based on these observations, we hypothesize that increased ROS, reduces expression of SMAD3 and CTGF, which results in reduction of type I collagen production, in fibroblasts in aged human skin. We propose four Specific Aims to test this hypothesis: 1) determine age-related alterations of ROS, SMAD3, CTGF, and type I collagen production, in human skin fibroblasts in vivo, 2) determine the ability of topical anti-oxidant to reduce ROS levels, mitigate impairment of the TGF-2/SMAD/CTGF axis, and induce type I collagen production, in aged human skin in vivo, 3) determine molecular mechanisms by which oxidative exposure reduces SMAD3, CTGF and type I collagen expression in human ski fibroblasts, and 4) determine molecular mechanisms by which CTGF regulates type I collagen expression. The results from the proposed studies will provide important insights regarding 1) the age of onset of human skin aging, 2) molecular actions of topical antioxidant, 3) mechanisms by which oxidative exposure regulates the TGF-2/SMAD/CTGF axis, and 4) molecular basis by which CTGF cooperates with TGF-2 in the regulation of type I collagen expression. PUBLIC HEALTH RELEVANCE: The long-term, broad goal of the proposed research is to understand the molecular basis of skin connective tissue aging. Age-dependent loss of skin collagen causes increased skin fragility and thereby makes skin more susceptible to bruising and impedes wound healing. The aging of the US population makes medical care of fragile skin a growing public health concern.
Funding Period: ----------------2009 - ---------------2014-
more information: NIH RePORT

Top Publications

  1. pmc Enhancing structural support of the dermal microenvironment activates fibroblasts, endothelial cells, and keratinocytes in aged human skin in vivo
    Taihao Quan
    Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109 5609, USA
    J Invest Dermatol 133:658-67. 2013
  2. pmc Expression of catalytically active matrix metalloproteinase-1 in dermal fibroblasts induces collagen fragmentation and functional alterations that resemble aged human skin
    Wei Xia
    Department of Dermatology, University of Michigan, 1301 E Catherine, R6447 Med Sci I, Ann Arbor, MI 48109 5609, USA
    Aging Cell 12:661-71. 2013
  3. pmc Elevated YAP and its downstream targets CCN1 and CCN2 in basal cell carcinoma: impact on keratinocyte proliferation and stromal cell activation
    Taihao Quan
    Department of Dermatology, University of Michigan, Ann Arbor, Michigan Electronic address
    Am J Pathol 184:937-43. 2014

Detail Information

Publications3

  1. pmc Enhancing structural support of the dermal microenvironment activates fibroblasts, endothelial cells, and keratinocytes in aged human skin in vivo
    Taihao Quan
    Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109 5609, USA
    J Invest Dermatol 133:658-67. 2013
    ..Thus, fibroblasts in aged human skin retain their capacity for functional activation, which is restored by enhancing structural support of the ECM...
  2. pmc Expression of catalytically active matrix metalloproteinase-1 in dermal fibroblasts induces collagen fragmentation and functional alterations that resemble aged human skin
    Wei Xia
    Department of Dermatology, University of Michigan, 1301 E Catherine, R6447 Med Sci I, Ann Arbor, MI 48109 5609, USA
    Aging Cell 12:661-71. 2013
    ....
  3. pmc Elevated YAP and its downstream targets CCN1 and CCN2 in basal cell carcinoma: impact on keratinocyte proliferation and stromal cell activation
    Taihao Quan
    Department of Dermatology, University of Michigan, Ann Arbor, Michigan Electronic address
    Am J Pathol 184:937-43. 2014
    ..Targeting YAP and/or CCN1 and CCN2 may provide clinical benefit in basal cell carcinoma. ..