Regulation of human sebaceous glands by 13-cis retinoic acid

描述(由申请人提供)：严重的痤疮可能会对数百万受影响的患者造成严重的心理和身体上的发病率。这项建议的目标是确定治疗痤疮的强效药物异维A酸如何在皮脂腺发挥作用。异维A酸(13-C/S维甲酸)是一种口服维甲酸，是针对这种疾病的每一种致病因素而对严重痤疮有效的唯一药物。13-c/S、维甲酸等口服维甲酸也用于癌症化疗。然而，异维甲酸是一种已知的致畸物质，其使用现在受到FDA强制登记系统的限制。由于缺乏对13-顺式维甲酸在皮脂腺中作用机制的了解，阻碍了寻找安全替代品的进展。我们的初步数据表明，13-顺式维甲酸诱导皮脂细胞凋亡和细胞周期停滞。基因芯片分析表明，13-cis RA可诱导多种天然免疫应答相关基因的表达，包括编码多功能分泌蛋白的Lipocalin 2，参与肾上皮形态发生、抵御细菌感染和细胞凋亡的中性粒细胞明胶酶相关Lipocalin(NGAL)。这个项目的主要目标是测试13-cis RA通过一个或多个代谢物作用于一个或多个代谢物以激活转录激活模式的假设，从而导致特异性作用于皮脂腺的凋亡介质的表达，如NGAL。目的1将使用我们的皮脂细胞模型系统来验证被广泛接受的假设，即13-c/S RA作为有效的维甲酸的储存库，在诱导细胞凋亡方面优于其单独的代谢产物。Subaim的目的是确定13-顺式视黄酸与全反式视黄酸的不同之处，以及13-顺式视黄酸诱导的细胞凋亡效应是否由维甲酸受体介导。目的2将检验NGAL是重要的细胞凋亡介质的假说，目的3将检验13-顺式维甲酸和NGAL对皮脂细胞的选择性凋亡反应是由于NGAL受体亚型的差异表达所致。这些研究的发现不仅有可能促进我们对维甲酸在痤疮中的作用的理解，而且可以促进对这些因素在癌症生物学和天然免疫方面的理解。

DESCRIPTION (provided by applicant): Severe acne can have profound psychological and physical morbidity for millions of affected patients. The goal of this proposal is to determine how isotretinoin, a potent drug for acne exerts its effects in the sebacous gland. Isotretinoin (13-c/s retinoic acid) is an oral retinoid that is the only agent effective against severe acne that targets each of the pathogenic factors of this disease. 13-c/s RA and other oral retinoids are also used in cancer chemotherapy. Isotretinoin however is a known teratogen whose use is now restricted within an FDA-mandated registry system. Lack of understanding of the mechanism of action of 13-cis RA in the sebaceous gland has hampered the progress to find safe alternatives. Our preliminary data indicate that 13-cis RA induces apoptosis and cell cycle arrest in sebocytes. Gene array expression analysis in sebocytes and in human skin indicates that 13-cis RA induces genes involved in the innate immune response, including lipocalin 2 that encodes a multifunctional secretory protein, neutrophil gelatinase associated lipocalin (NGAL) involved in renal epithelial morphogenesis, defense against bacterial pathogens and in apoptosis. The major goal of this project is to test the hypothesis that 13- cis RA acts by a metabolite or metabolites to activate a pattern of transcriptional activation leading to the expression of apoptotic mediators, such as NGAL, that act specifically on sebaceous glands. Aim 1 will use our sebocyte model system to test the widely held hypothesis that 13- c/s RA, as a reservoir of potent retinoids, is superior to its individual metabolites in inducing apoptosis. Subaims are directed determining how 13-cis RA differs from all-trans RA and whether the apoptotic effects induced by 13-cis RA are mediated by retinoid receptors. Aim 2 will test the hypothesis that NGAL is an important mediator of apoptosis and Aim 3 will test the hypothesis that the sebocyte-selective apoptotic response to 13- cis RA and NGAL is due to differential expression of NGAL receptor isoforms. The findings of these studies not only have the potential to advance our understanding of retinoid action in acne, but can lead to advances in the understanding of these agents in cancer biology and in innate immunity as well.