A Lipoxygenase Pathway in Epidermal Differentiation

表皮分化中的脂氧合酶途径

• 批准号: 7091698
• 负责人: ALAN R. BRASH
• 金额: $ 26.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091698
• 关键词: cell differentiation; cell growth regulation; clinical research; enzyme activity; enzyme induction /repression; enzyme mechanism; epoxide hydrolase; fluorescence microscopy; human subject; human tissue; keratinocyte; linoleate; lipoxygenase; molecular biology; peroxisome proliferator activated receptor; protein localization; tissue /cell culture

DESCRIPTION (provided by applicant): The lipoxygenase (LOX) family of enzymes has well established roles in inflammation (5-LOX and the leukotrienes), and yet-to-be fully defined roles in cell differentiation and proliferation. The recent finding of a human genetic defect in two LOX enzymes associated with an inherited form of ichthyosis presents an opportunity to connect the functioning of these enzymes with a role in epidermal differentiation. The genetics identifies both 12R-LOX and eLOX3 (epidermal lipoxygenase-3) as defective in the families studied, and by implication, as playing a critical and important role in all normal individuals. We recently found a plausible biochemical explanation for the genetics: the two lipoxygenases, 12R-LOX and eLOX3 act in tandem to convert arachidonic acid to a specific epoxyalcohol metabolite. Here we propose to investigate the role of this LOX pathway, pursuing the overall hypothesis that it has a vital function in keratinocyte differentiation, by characterizing substrates, intermediates, and products of the intertwined LOX activities, and the ability of these metabolites to activate or modulate the differentiation process in keratinocytes. The Specific Aims are: To characterize the enzymology and pathways of metabolism involving 12R-LOX and eLOX3; To determine the functional relationships between 12R-LOX and eLOX3 by analyses of their expression, activities and localization in cells and tissues; To determine the biological activities of the 12R-LOX/eLOX3-derived products The failure of keratinocytes to correctly differentiate is a hallmark of severe skin diseases like psoriasis or ichthyosis. The results of this study will help characterize a model for LOX enzyme activity in controlling cell differentiation in a well-defined human context of disease, as well as uncovering the activities of a new class of agents, epoxyalcohols and their derivatives, with the potential for future therapeutic interventions.

描述（由申请人提供）：脂氧合酶（LOX）家族在炎症（5-LOX和白三烯）中具有明确的作用，并且在细胞分化和增殖中的作用尚未完全确定。最近发现两种与遗传性鱼鳞病相关的 LOX 酶存在人类遗传缺陷，这为将这些酶的功能与表皮分化中的作用联系起来提供了机会。遗传学鉴定出 12R-LOX 和 eLOX3（表皮脂氧合酶-3）在所研究的家族中均存在缺陷，并且暗示在所有正常个体中都发挥着至关重要的作用。我们最近发现了一个合理的遗传学生化解释：两种脂氧合酶 12R-LOX 和 eLOX3 协同作用，将花生四烯酸转化为特定的环氧醇代谢物。在这里，我们建议通过表征相互交织的 LOX 活性的底物、中间体和产物，以及这些代谢物激活或调节的能力，研究该 LOX 途径的作用，追求其在角质形成细胞分化中具有重要功能的总体假设。角质形成细胞的分化过程。具体目标是： 表征涉及 12R-LOX 和 eLOX3 的酶学和代谢途径； 通过分析12R-LOX和eLOX3在细胞和组织中的表达、活性和定位来确定它们之间的功能关系；确定 12R-LOX/eLOX3 衍生产品的生物活性 角质形成细胞无法正确分化是牛皮癣或鱼鳞病等严重皮肤病的标志。这项研究的结果将有助于表征在明确的人类疾病背景下控制细胞分化的 LOX 酶活性模型，并揭示一类新型试剂、环氧醇及其衍生物的活性，具有潜在的未来的治疗干预。