Regulation of Lipid Metabolism in Human Sebaceous Glands

描述（由申请人提供）：痤疮是最常见的皮肤病 影响年轻人。除了心理上的痛苦和 低自尊，痤疮会导致永久性的面部疤痕。生产 皮脂腺分泌的皮脂（油）是痤疮发生的关键因素。 除了异维甲酸和激素治疗，没有药物， 有效减少皮脂产生。不幸的是，这些药物 严重的副作用，包括出生缺陷。最近没有任何进展 在我们的能力，以治疗减少皮脂生产的部分原因是， 我们对调节人体皮脂的机制缺乏了解 生产本研究的总体目标是阐明 其调节人皮脂产生以鉴定新治疗剂 其药理学配体将提供安全有效的靶向部位 用于治疗痤疮的异维甲酸的替代品。过氧化物酶 增殖物激活受体（PPARs）和甾醇反应元件结合 SREBPs是脂质代谢的关键转录调节因子， 各种组织。待检验的中心假设是PPARs调节 人体皮脂腺的脂质代谢。亚油酸和 其它的PPAR激动剂对脂质代谢的影响将使用以下测定来确定： 脂质转运、合成和代谢，以及基因分析， 表情13-顺式视黄酸是最有效的皮脂抑制剂。 PPARs和类维生素A具有共同的DNA结合位点，在这方面， 介导共同基因的转录。我们的第二个假设是13-顺式 视黄酸通过改变 PPAR-regulated genes. 13-顺式维甲酸对基因表达的影响 将在人皮脂腺细胞和接受以下治疗的患者的皮肤中进行检查： 异维甲酸从拟议的实验中产生的数据将推进我们的研究。 了解调节皮脂产生的机制，并可能导致 确定潜在的其他治疗靶点， 痤疮的治疗

DESCRIPTION (provided by the applicant): Acne is the most common skin disease affecting young people. In addition to psychological distress and feelings of low self-esteem, acne can lead to permanent facial scarring. The production of sebum (oil) by sebaceous glands is a key factor in the development of acne. Apart from isotretinoin and hormonal therapy, there are no drugs that effectively reduce sebum production. Unfortunately, these drugs have significant side effects, including birth defects. No recent advances have been made in our ability to therapeutically reduce sebum production in part due to our lack of knowledge regarding the mechanisms regulating human sebum production. The overall goal of this research is to elucidate the mechanisms that regulate human sebum production in order to identify novel therapeutic target sites whose pharmacological ligands will offer safe and effective alternatives to isotretinoin for the treatment of acne. Peroxisome proliferator-activated receptors (PPARs) and sterol response element binding proteins (SREBPs) are key transcriptional regulators of lipid metabolism in a variety of tissues. The central hypothesis to be tested is that PPARs regulate lipid metabolism in human sebaceous glands. The effects of linoleic acid and other PPAR agonists on lipid metabolism will be determined using assays of lipid transport, synthesis, and catabolism in addition to an analysis of gene expression. 13-cis retinoic acid is the most potent sebosuppressive agent. PPARs and retinoids share common DNA binding sites, and in this regard can mediate transcription of common genes. Our secondary hypothesis is that 13-cis retinoic acid reduces sebum production by altering the expression of PPAR-regulated genes. The effects of 13-cis retinoic acid on gene expression will be examined in human sebocytes and in skin from patients treated with isotretinoin. Data generated from the proposed experiments will advance our understanding of the mechanisms regulating sebum production and can lead to identification of potential additional therapeutic target sites in the treatment of acne.