Role of PPARgamma in ultraviolet stress responses

描述(由申请人提供)： 紫外线B(UVB)照射是皮肤肿瘤的主要原因，也是治疗银屑病等炎症性皮损的有效方法。我们最近发现，UVB暴露是配体激活的转录调节因子--过氧化物酶体增殖物激活的受体-伽马(PPARGamma)的有效激活剂。因此，PPARγ激活可能在调节UVB介导的表皮细胞应激反应中起关键作用。根据这一观点，我们在两种不同的细胞系，包括原代角质形成细胞(PHKs)中发现，UVB介导的环氧合酶-2(COX-2)的诱导是依赖PPAR的。此外，我们还发现，西格列酮是一类常用的抗糖尿病PPAR-γ激动剂，它也能够诱导PHK中COX-2的表达。鉴于UVB、COX-2和PPARGamma都被证明可以独立地改变细胞的生长、分化和凋亡，我们假设许多UVB介导的细胞应激反应可能是由于PPARGamma的激活，或者是COX-2依赖的，或者是独立的。根据这一假设，我们提供了PPARγ改变角质形成细胞分化和凋亡的证据。在这项资助申请中，我们建议进一步定义这些UVB介导的细胞应激反应中的哪些是PPAR伽马依赖的。这将使用体外和体内模型来研究PPARγ的激活如何改变细胞的生长、分化和凋亡。这将在UVB介导的PPARGamma激活以及单独激活PPARGamma的背景下进行。COX-2的诱导在这些过程中的作用也将被研究。这些研究尤其重要，因为最近的研究表明，几种通常用于治疗II型糖尿病的PPAR伽马激动剂可能具有癌症化学预防活性，也可能是有效的抗牛皮癣药物。这些数据可以用于未来的研究，重点是确定PPARGamma系统是增强还是抑制UVB光癌发生，以及确定PPARGamma在UVB介导的炎症性皮肤病治疗中扮演什么角色。鉴于II型糖尿病发病率的增加，以及长期使用PPAR伽马激动剂治疗这些患者的需要，更好地了解这些药物在UVB光癌发生中所起的作用尤为重要。

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.