Role of PPARgamma in ultraviolet stress responses

PPARγ 在紫外线应激反应中的作用

基本信息

批准号：
7460816
负责人：
RAYMOND L KONGER
金额：
$ 7.4万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7460816
关键词：
Acute Affect Agonist Anti-psoriatic Agent Apoptosis Applications Grants Biological Models Cell Line Cellular Stress Response Chemopreventive Agent Chronic Class Clinical Cutaneous Data Development Dinoprostone Epidermis Future Gene Targeting Goals Homeostasis Hormones Human Hyperplasia In Vitro Inbred NOD Mice Inflammatory Ionizing radiation Lead Left Lesion Ligands Light Lipids Malignant Neoplasms Mediating Mediator of activation protein Modality Modeling Neoplasms Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Oxygen PPAR gamma Pathologic Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Play Process Production Promoter Regions Prostaglandin Production Prostaglandin-Endoperoxide Synthase Psoriasis RXR Rate Role Signal Transduction Skin Solar Energy Stream System Thinking Ultraviolet Rays Xenograft procedure biological adaptation to stress cell growth ciglitazone coping cyclooxygenase 1 cyclooxygenase 2 diabetic in vivo Model keratinocyte keratinocyte differentiation member neoplastic novel response skin disorder ultraviolet

项目摘要

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.

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，也是牛皮癣等炎症性皮肤病变的有效治疗方式。我们最近表明，UVB暴露是配体激活的转录调节剂，过氧化物酶体增殖物激活受体伽马（PPARGAMMA）的有效活化剂。因此，ppargamma激活在调节表皮中的UVB介导的细胞应激反应中可能起关键作用。与这个想法一致，我们已经以两种不同的细胞系（包括原代角质形成细胞（PHK））显示了UVB介导的环氧酶2（COX-2）诱导是PPARGAMMA依赖性的。此外，我们表明，Ciglitazone是常见类别的抗糖尿病性ppargamma激动剂的成员，也能够在PHKS中诱导COX-2表达。鉴于UVB，COX-2和PPARGAMMA均已证明可以独立改变细胞的生长，分化和凋亡，因此我们假设许多这些UVB介导的细胞应激反应可能是由于PPARGAMMA激活所致，这是在COX-2-2依赖或独立的时尚。根据这一假设，我们提供了ppargamma改变角质形成细胞分化和凋亡的证据。在此赠款应用中，我们建议进一步定义这些UVB介导的细胞应力反应中的哪些是ppargamma的。这将使用体外和体内模型同时研究，以检查ppargamma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的情况下进行。还将检查COX-2诱导在这些过程中的作用。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PPARGAMMA激动剂可能具有癌症化学预防活性，并且也可能是有效的抗PSoriatic剂。然后，这些数据可用于将未来的研究集中在确定PPARGAMMA系统是否增加或抑制UVB光碳纤维促促症状，并确定ppargamma在UVB介导的炎症性皮肤病治疗中的作用。鉴于II型糖尿病的发生率不断提高，并且需要长期使用PPARGAMMA激动剂来治疗这些患者，因此对这些药物在UVB光致促促炎中的作用有更深入的了解，这一点尤其重要。