Modulation of skin cancer by PPARb/d

描述（由申请人提供）：仍然明显需要开发新的皮肤癌化学预防策略，皮肤癌是人类最常见的癌症形式之一。在前一个资助周期中，我们鉴定并表征了天然脂肪酸，其可以作为皮肤中过氧化物酶体增殖物激活受体（PPAR）的内源性配体。此外，我们证明，配体激活的过氧化物酶体增殖物激活受体可以有效地抑制化学诱导的皮肤癌，这种化学预防活性的基础机制包括过氧化物酶体增殖物激活受体依赖的癌前细胞有丝分裂的衰减和炎症信号的调制。这种抑制机制的选择性与初步数据相结合，强烈表明激活PPAR <$/<$也可能对靶向突变型p53细胞有效。以前的研究集中在化学诱导的皮肤癌，但紫外线（UV）是导致人类皮肤癌的最常见病原体。因此，目前的建议是建立在我们以前的研究结果，通过检查的机制作用的过氧化物酶体增殖物激活物受体在紫外线诱导的皮肤癌。该建议的中心假设是，靶向PPAR/与饮食中常见的天然配体可以通过调节细胞周期和通过与炎症信号的表观遗传相互作用有效地预防UV诱导的皮肤癌。具体目标1将决定是否可以有针对性地防止紫外线诱导的皮肤癌。这将包括分析，将确定是否激活过氧化物酶体增殖物激活受体与合成或天然配体可以预防和/或抑制紫外线诱导的皮肤癌。特异性目标2将确定激活的PPAR/是否可以优先靶向p53突变细胞以预防UV诱导的皮肤癌。这将包括分析，以确定PPAR <$/<$是否可以预防和/或逆转角质形成细胞中突变型p53的形成，是否靶向基底角质形成细胞中的PPAR <$/<$抑制p53突变型斑块，以及PPAR <$/<$与p107/p130的相互作用是否介导具有突变型p53的细胞的优先靶向。具体目标3将确定在角质形成细胞中通过PPAR的促炎信号传导的衰减是否抑制UV诱导的皮肤癌。这将包括确定非PPRE驱动的PPAR/机制（表观遗传）是否抑制角质形成细胞中UVB诱导的促炎信号传导，以及非PPRE驱动的PPAR/机制是否抑制UVB诱导的皮肤癌的分析。该分析将利用独特的转基因模型和基于细胞的模型来测试这些假设。这些新的和创新的研究结果将为未来的临床试验提供框架，这些临床试验将靶向与皮肤癌化学预防的其他分子靶点结合的PPAR。此外，这些结果可以为筛选有效的化合物提供框架，这些化合物可以激活PPRE驱动的和/或表观遗传途径，以选择性地调节用于化学预防的PPAR <$/<$。

DESCRIPTION (provided by applicant): There remains a distinct need to develop new chemopreventive strategies for skin cancer, one the most commonly diagnosed forms of cancer in humans. During the previous funding cycle, we identified and characterized natural fatty acids that can act as endogenous ligands for peroxisome proliferator- activated receptor-¿/¿ (PPAR¿/¿) in skin. Moreover, we demonstrated that ligand activation of PPAR¿/¿ can effectively inhibit chemically-induced skin cancer, and that the mechanisms that underlie this chemopreventive activity include PPAR¿/¿ dependent attenuation of mitosis in premalignant oncogenic cells and modulation of inflammatory signaling. The selective nature of this inhibitory mechanism coupled with preliminary data strongly suggest that activating PPAR¿/¿ may also be effective for targeting cells with mutant p53. The former studies focused on chemically-induced skin cancer, but ultraviolet light (UV) represents the most common etiological agent causing skin cancer in humans. Thus, the present proposal builds on our former findings by examining the mechanistic role of PPAR¿/¿ in UV-induced skin cancer. The central hypothesis of this proposal is that targeting PPAR/ with a natural ligand commonly found in the diet can effectively prevent UV-induced skin cancer by modulation of the cell cycle and by epigenetically interacting with inflammatory signaling. Specific Aim 1 will determine whether PPAR¿/¿ can be targeted to prevent UV-induced skin cancer. This will include analysis that will determine whether activating PPAR¿/¿ with synthetic or natural ligands can prevent and/or inhibit UV-induced skin cancer. Specific Aim 2 will determine whether activating PPAR/ can preferentially target p53 mutant cells to prevent UV-induced skin cancer. This will include analysis that will determine whether PPAR¿/¿ can prevent and/or regress mutant p53 formation in keratinocytes, whether targeting PPAR¿/¿ in basal keratinocyte inhibits p53 mutant patches, and whether PPAR¿/¿ interactions with p107/p130 mediated preferential targeting of cells with mutant p53. Specific Aim 3 will determine if attenuation of pro-inflammatory signaling by PPAR/ in keratinocytes inhibits UV-induced skin cancer. This will include analysis that will determine whether a non-PPRE driven PPAR/ mechanism (epigenetic) inhibits UVB- induced pro-inflammatory signaling in keratinocytes, and whether a non-PPRE driven PPAR¿/¿ mechanism inhibits UVB-induced skin cancer. This analysis will take advantage of unique transgenic models and cell based models to test these hypotheses. Results from these novel and innovative studies will provide the framework for future clinical trials that will target PPAR¿/¿ in conjunction with other molecular targets for skin cancer chemoprevention. Moreover, results could provide framework for screening of effective compounds that can activate either PPRE-driven and/or epigenetic pathways for selective modulation of PPAR¿/¿ for chemoprevention.