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，开发新的化学预防策略仍然是一个明显的需要。在之前的资助周期中，我们鉴定并表征了天然脂肪酸，这些脂肪酸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，我们证明了PPAR配体激活可以有效地抑制化学诱导的皮肤癌，并且这种化学预防活性的机制包括PPAR依赖于恶性肿瘤前细胞有丝分裂的衰减和炎症信号的调节。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p53突变细胞有效。以前的研究主要集中在化学诱发的皮肤癌上，但紫外线（UV）是导致人类皮肤癌的最常见的病因。因此，目前的建议建立在我们以前的研究结果的基础上，通过研究PPAR在紫外线诱发皮肤癌中的机制作用。该提案的核心假设是，用饮食中常见的天然配体靶向PPAR/，可以通过调节细胞周期和表观遗传与炎症信号的相互作用，有效预防紫外线诱导的皮肤癌。Specific Aim 1将确定PPAR是否可以靶向预防紫外线诱发的皮肤癌。这将包括确定用合成或天然配体激活PPAR是否可以预防和/或抑制紫外线诱发的皮肤癌的分析。特异性Aim 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¿/¿是否可以预防和/或逆转角化细胞中突变p53的形成，是否靶向基础角化细胞中的PPAR¿/¿抑制p53突变斑块，以及PPAR¿/¿与p107/p130的相互作用是否介导了p53突变细胞的优先靶向。特异性Aim 3将确定角化细胞中PPAR/的促炎信号衰减是否抑制紫外线诱导的皮肤癌。这将包括分析非ppre驱动的PPAR/机制（表观遗传）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。本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，这些临床试验将把PPAR与其他分子靶点结合起来，用于皮肤癌的化学预防。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驱动和/或表观遗传途径，选择性地调节PPAR进行化学预防。

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.