Modulation of skin cancer by PPARb/d

描述(由申请人提供)：皮肤癌是人类最常见的癌症之一，仍有明显的需要开发新的化学预防策略。在之前的资金周期中，我们识别并表征了天然脂肪酸，它们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，我们还证明了PPAR的配体激活可以有效地抑制化学诱导的皮肤癌，这种化学预防作用的机制包括PPAR？/？依赖于抑制癌前细胞的有丝分裂和调节炎症信号。这种抑制机制的选择性结合初步数据有力地表明，激活PPAR也可能有效地靶向带有突变的p53的细胞。以前的研究集中在化学诱导的皮肤癌上，但紫外线(UV)是导致人类皮肤癌的最常见的病原体。因此，目前的建议建立在我们以前的发现的基础上，通过研究PPAR在紫外线诱导的皮肤癌中的机制作用。这一建议的中心假设是，通过调节细胞周期和表观遗传与炎症信号的相互作用，靶向PPAR/与饮食中常见的天然配体可以有效地预防紫外线诱导的皮肤癌。具体目标1将确定PPAR是否可以靶向预防紫外线诱导的皮肤癌。这将包括确定用合成或天然配体激活PPAR是否可以预防和/或抑制紫外线诱导的皮肤癌的分析。特异性目标2将确定激活PPAR/是否可以优先靶向P53突变细胞来预防紫外线诱导的皮肤癌。这将包括确定PPAR是否可以防止和/或逆转角质形成细胞中突变的P53的形成，靶向基础角质形成细胞中的PPAR是否抑制P53突变补丁，以及PPAR和p107/p130的相互作用是否介导具有突变P53的细胞的优先靶向。具体目标3将确定角质形成细胞中PPAR/的致炎信号减弱是否抑制紫外线诱导的皮肤癌。这将包括确定非PPRE驱动的PPAR/机制(表观遗传学)是否抑制UVB诱导的角质形成细胞中的促炎信号，以及非PPRE驱动的PPAR/机制是否抑制UVB诱导的皮肤癌。这项分析将利用独特的转基因模型和基于细胞的模型来检验这些假设。这些新颖和创新的研究结果将为未来的临床试验提供框架，这些试验将与皮肤癌化学预防的其他分子靶点一起针对PPAR？/？此外，这些结果可以为筛选能够激活PPRE驱动的和/或表观遗传途径的有效化合物提供框架，以选择性地调节PPAR？/？用于化学预防。

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.