Ultraviolet (UV) irradiation from the sun damages human skin connective tissue and causes premature skin aging (photoaging). Photoaging exists in nearly all adult individuals and is therefore a significant public health concern. In photodamaged skin, damaged connective tissue impairs normal skin function and creates a tissue environment conducive to formation of skin cancer. We have demonstrated UV irradiation reduces synthesis of type I procollagen and elevates expression of matrix-degrading metalloproteinases (MMPs), which degrade type I collagen, the most abundant structural protein in the dermis. The molecular mechanisms responsible for these skin connective tissue abnormalities in photoaged skin are far from clear. We find that the cysteine-rich protein 61 (CYR61), a secreted, extracellular matrix (ECM)-associated protein, is a novel mediator of collagen homeostasis. CYR61 is predominantly expressed in human skin dermal fibroblast, and is substantially elevated in the dermis of photoaged and acutely UV-irradiated human skin in vivo, and in UV-irradiated human skin fibroblasts. The function of CYR61 in human skin has not previously been studied. Our preliminary data indicate that CYR61 exerts dual effects on collagen homeostasis by inhibiting type I collagen production and promoting MMP-1-mediated collagen degradation, thereby causing a net deficit of dermal collagen, a prominent feature of photoaged human skin. Based on our data we hypothesize that secreted CYR61 avidly associates with EMC, and functions through integrins aV?3 and aV?5 to regulate collagen homeostasis. To test this hypothesis, four specific aims will be carried out:
Specific Aim 1 seeks to determine the mechanisms by which UV irradiation up-regulates CYR61 expression. We will identify regulatory elements and cis-acting factors that mediate UV irradiation up-regulation of CYR61 gene transcription.
Specific Aim 2 will determine CYR61 protein functional domain(s) involved in regulation of collagen homeostasis.
Specific Aim 3 will determine the molecular mechanisms by which CYR61 functions through integrin-mediated pathways to regulate collagen homeostasis. Finally, Specific Aim 4 will use overexpression, knock-down, and pharmacological inhibitors to determine the role and relative contributions of multiple pathways involved in collagen and MMP-1 regulation in CYR61-mediated aberrant collagen homeostasis. Results from the proposed studies will provide a foundation of knowledge regarding the role of CYR61 in human skin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES014697-04
Application #
7878714
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (02))
Program Officer
Humble, Michael C
Project Start
2007-09-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$331,808
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
Shao, Yuan; Qin, Zhaoping; Alexander Wilks, James et al. (2018) Physical properties of the photodamaged human skin dermis: Rougher collagen surface and stiffer/harder mechanical properties. Exp Dermatol :
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
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
Quan, Chunji; Cho, Moon Kyun; Perry, Daniel et al. (2015) Age-associated reduction of cell spreading induces mitochondrial DNA common deletion by oxidative stress in human skin dermal fibroblasts: implication for human skin connective tissue aging. J Biomed Sci 22:62
Quan, Chunji; Cho, Moon Kyun; Shao, Yuan et al. (2015) Dermal fibroblast expression of stromal cell-derived factor-1 (SDF-1) promotes epidermal keratinocyte proliferation in normal and diseased skin. Protein Cell 6:890-903
Qin, Zhaoping; Okubo, Toru; Voorhees, John J et al. (2014) Elevated cysteine-rich protein 61 (CCN1) promotes skin aging via upregulation of IL-1? in chronically sun-exposed human skin. Age (Dordr) 36:353-64
Qin, Zhaoping; Robichaud, Patrick; He, Tianyuan et al. (2014) Oxidant exposure induces cysteine-rich protein 61 (CCN1) via c-Jun/AP-1 to reduce collagen expression in human dermal fibroblasts. PLoS One 9:e115402
Quan, Taihao; Xu, Yiru; Qin, Zhaoping et al. (2014) Elevated YAP and its downstream targets CCN1 and CCN2 in basal cell carcinoma: impact on keratinocyte proliferation and stromal cell activation. Am J Pathol 184:937-943
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

Showing the most recent 10 out of 13 publications