| Budget Amount *help |
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Activation of MAP Kinase in skin plays a critical role for skin proliferation. Raf is one of the upstream effectors of MAPK signaling that induce epidermal hyperplasia. We previously characterized Kl4RafERtm transgenic mice bearing the 4-hydroxytamoxifen (4OHT)-responsive mutant ER ligand binding domain-Raf fusion gene under control of the keratin 14 promoter. A single topical application of 4OHT induced the epidermis-specific expression of Phosphorylated active ERK 1/2, a downstream factor of Raf signaling, in those mice within 8-12 hrs. Massive hyperplasia with hyperkeratosis and suppressed differentiation of the epidermis developed within 7 days. The inflammatory changes were also seen in these mice with 4-OHT treatments. We imported these mice from Dr. khavari rab at U. S. A.. At first we checked whether applying MAPK inhibitors in mouse skin reduced these phenomenon. We applied PD98059, genistein, LY294002, apigenin, SB202190, and SB203580, the MAPK and related gene inhibitors, with 4-hydroxy-tamoxifen (4-OHT) in Kl4RafERtm transgenic mice skin. But there is no significant difference between both-applied and only 4-hydroxy-tamoxifen applied transgenic mice skin. Next we applied cortico steroids ointment with 4-OHT in these mice. The acantosis of the skin and inflammation were diminished with treatment of cortico steroids. To investigate these skin condition, we purified the protein in 4-OHT treated skin lesions and checked cytokine level. IL-18, IL-15 and MCP-1 levels were increased in the skin lesions and IFN-γ and IL-17 were induced in T cells of the draining lymph nodes. Thus, the induction of Raf in the epidermis causes not only keratinocyte hyper proliferation but also psoriasis-like inflammatory conditions of the skin.
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