Regulation of Lipid Metabolism in Human Sebaceous Glands

简介(申请人提供)：粉刺是最常见的皮肤病 影响着年轻人。除了心理上的痛苦和感受之外 缺乏自尊，粉刺会导致面部永久性疤痕。产品的生产 皮脂腺产生的皮脂(油)是痤疮发生的关键因素。 除了异维A酸和激素疗法外，没有其他药物可以 有效减少皮脂生成。不幸的是，这些药物 严重的副作用，包括出生缺陷。最近没有取得任何进展 我们通过治疗减少皮脂产生的能力，部分原因是 我们对调节人体皮脂的机制缺乏了解 制作。本研究的总体目标是阐明这一机制。 调节人类皮脂产生，以确定新的治疗方法 其药理配体将提供安全有效的靶点 治疗痤疮的异维A酸替代品。过氧酶体 增殖物激活受体(PPAR)与固醇反应元件结合 蛋白质(SREBPs)是脂类代谢的关键转录调节因子。 各种各样的纸巾。需要检验的中心假设是PPAR调节 人类皮脂腺中的脂类代谢。亚油酸和亚油酸的作用 其他影响脂代谢的PPAR激动剂将通过以下方法确定 除了基因分析外，脂类的运输、合成和分解代谢 表情。13-顺式维甲酸是最有效的降脂剂。 PPAR和维甲酸共享共同的DNA结合位点，在这方面可以 调节常见基因的转录。我们的第二个假设是13-顺式 维甲酸通过改变皮质醇的表达减少皮脂的产生 PPAR调节的基因。13-顺式维甲酸对基因表达的影响 将在人类皮脂细胞和患者的皮肤中进行检测 异维甲酸。从拟议的实验中产生的数据将推动我们的 了解调节皮脂产生的机制，并可导致 确定潜在的额外治疗靶点在 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.