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. ? ? ?
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