Regulation of human sebaceous glands by 13-cis retinoic acid

描述（由申请人提供）：严重痤疮对数百万受影响的患者具有深刻的心理和生理疾病。这项提议的目的是确定异维甲酸，一种有效的痤疮药物如何在皮脂腺中发挥其作用。异维甲酸（13-c/s维甲酸）是一种口服类维甲酸，是唯一有效对抗严重痤疮的药物，针对这种疾病的每个致病因素。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物，目前在fda授权的注册系统中被限制使用。缺乏对13-顺式RA在皮脂腺中的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RA可诱导脂细胞凋亡和细胞周期阻滞。皮脂细胞和人皮肤的基因阵列表达分析表明，13顺式RA诱导参与先天免疫反应的基因，包括编码一种多功能分泌蛋白的脂钙蛋白2，参与肾上皮形态发生、细菌病原体防御和细胞凋亡的中性粒细胞明胶酶相关脂钙蛋白（NGAL）。该项目的主要目标是验证13-顺式RA通过代谢物或代谢物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（如NGAL）的表达。目的1将使用我们的皮脂细胞模型系统来验证广泛持有的假设，即13- c/s RA作为强效类维生素a的储存库，在诱导细胞凋亡方面优于其单个代谢物。子目的旨在确定13-顺式RA与全反式RA的差异，以及13-顺式RA诱导的凋亡效应是否由类视黄醛受体介导。Aim 2将验证NGAL是细胞凋亡的重要介质的假设，Aim 3将验证脂质细胞对13-顺式RA和NGAL的选择性凋亡反应是由于NGAL受体亚型的差异表达的假设。这些研究的发现不仅有可能促进我们对类维生素a在痤疮中的作用的理解，而且还可能导致对这些药物在癌症生物学和先天免疫中的理解的进步。

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.