Regulation of human sebaceous glands by 13-cis retinoic acid

描述（由申请人提供）：严重痤疮可能对数百万受影响的患者造成严重的心理和身体疾病。这项建议的目的是确定如何异维甲酸，一个有效的药物痤疮发挥其作用，在皮脂腺。异维甲酸（13-c/s维甲酸）是一种口服类维生素A，是唯一有效对抗严重痤疮的药物，针对这种疾病的每一种致病因素。13-c/s RA和其他口服类维生素A也用于癌症化疗。然而，异维甲酸是一种已知的致畸剂，其使用现在被限制在FDA授权的注册系统内。对13-顺式RA在皮脂腺中的作用机制缺乏了解，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RA诱导皮脂腺细胞凋亡和细胞周期阻滞。在皮脂腺细胞和人皮肤中的基因阵列表达分析表明，13-顺式RA诱导参与先天性免疫应答的基因，包括编码多功能分泌蛋白的脂质运载蛋白2、参与肾上皮形态发生、防御细菌病原体和细胞凋亡的中性粒细胞明胶酶相关脂质运载蛋白（NGAL）。该项目的主要目标是测试13-顺式RA通过代谢物或代谢物激活转录激活模式导致细胞凋亡介导物（如NGAL）表达的假说，所述细胞凋亡介导物特异性作用于皮脂腺。目的1将使用我们的皮脂腺细胞模型系统来测试广泛持有的假设，即13- c/s RA，作为一个水库的有效的类维生素A，是上级其个别代谢产物诱导细胞凋亡。本研究旨在确定13-顺式RA与全反式RA的不同之处以及13-顺式RA诱导的凋亡效应是否由维甲酸受体介导。目的2将测试NGAL是细胞凋亡的重要介质的假设，目的3将测试对13-顺式RA和NGAL的皮脂细胞选择性细胞凋亡反应是由于NGAL受体亚型的差异表达的假设。这些研究的结果不仅有可能促进我们对痤疮中类维生素A作用的理解，而且还可能导致对癌症生物学和先天免疫中这些药物的理解的进步。

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.