Role of PPARgamma in ultraviolet stress responses

描述（由申请人提供）： 紫外线B（UVB）暴露是皮肤肿瘤的主要原因，也是一种有效的治疗炎症性皮肤病变，如银屑病。我们最近发现，UVB照射是配体激活的转录调节因子过氧化物酶体增殖物激活受体-γ（PPARgamma）的有效激活剂。因此，PPARgamma激活可能在调节表皮中UVB介导的细胞应激反应中起关键作用。根据这一想法，我们已经在两种不同的细胞系，包括原代角质形成细胞（PHK），UVB介导的环氧合酶2（考克斯-2）诱导是PPARgamma依赖性的。此外，我们表明，环格列酮，一个成员的抗糖尿病的PPARgamma激动剂，也能够诱导考克斯-2的表达在PHKs。考虑到UVB、考克斯-2和PPARgamma均被证明能独立改变细胞生长、分化和凋亡，我们推测许多UVB介导的细胞应激反应可能是由于PPARgamma的激活，无论是以考克斯-2依赖还是独立的方式。根据这一假设，我们提供的证据表明，PPARgamma改变角质形成细胞的分化和凋亡。在本申请中，我们建议进一步确定这些UVB介导的细胞应激反应是PPARgamma依赖的。这将使用体外和体内模型来完成，以检查PPARgamma的激活如何改变细胞生长、分化和凋亡。这将在UVB介导的PPARgamma活化以及单独的PPARgamma活化的情况下进行。考克斯-2诱导在这些过程中的作用也将进行检查。这些研究特别重要，因为最近的研究表明，通常用于治疗II型糖尿病的几种PPARgamma激动剂可能具有癌症化学预防活性，也可能是有效的抗银屑病药物。然后，这些数据可以用于将未来的研究重点放在确定PPARgamma系统是否增强或抑制UVB光致癌作用上，以及确定PPARgamma在UVB介导的炎症性皮肤病治疗中起什么作用。鉴于II型糖尿病发病率的增加以及需要长期使用PPARgamma激动剂治疗这些患者，更好地了解这些药物在UVB光致癌作用中的作用尤为重要。

DESCRIPTION (provided by applicant): Ultraviolet B (UVB) exposure is the primary cause of cutaneous neoplasia and also is an effective treatment modality for inflammatory skin lesions like psoriasis. We have recently shown that UVB exposure is a potent activator of the ligand-activated transcriptional regulator, peroxisome proliferator activated receptor-gamma (PPARgamma). Thus, PPARgamma activation may play a key role in regulating UVBmediated cellular stress responses in the epidermis. In line with this idea, we have shown in two different cell lines, including primary keratinocytes (PHKs), that UVB mediated cyclooxygenase 2 (COX-2) induction is PPARgamma dependent. Moreover, we show that ciglitazone, a member of a commonly prescribed class of anti-diabetic PPARgamma agonists, is also capable of inducing COX-2 expression in PHKs. Given that UVB, COX-2, and PPARgamma have all been shown to independently alter cellular growth, differentiation, and apoptosis, we hypothesize that many of these UVB-mediated cellular stress responses may be due to PPARgamma activation, either in a COX-2 dependent or independent fashion. In line with this hypothesis, we provide evidence that PPARgamma alters keratinocyte differentiation and apoptosis. In this grant application, we propose to further define which of these UVB-mediated cellular stress responses are PPARgamma dependent. This will be done using both in vitro and in vivo models to examine how activation of PPARgamma alters cellular growth, differentiation and apoptosis. This will be done both in the context of UVB-mediated PPARgamma activation, as well activation of PPARgamma alone. The role of COX-2 induction in these processes will also be examined. These studies are particularly important given that recent studies indicate that several PPARgamma agonists commonly used to treat type II diabetes may have cancer chemopreventive activity and may also be effective anti-psoriatic agents. This data can then be used to focus future studies on determining whether the PPARgamma system augments or suppresses UVB photocarcinogenesis, as well as determine what role PPARgamma plays in UVB-mediated treatment of inflammatory skin disease. Given the increasing rates of type II diabetes and the need to treat these patients over the long term with PPARgamma agonists, it is particularly important to have a greater understanding of the role these agents play in UVB photocarcinogenesis.