OMEGA HYDROXY CERAMIDES IN EPIDERMAL DIFFERENTIATION AND FUNCTION

OMEGA 羟基神经酰胺在表皮分化和功能中的作用

• 批准号: 6197175
• 负责人: WALTER M HOLLERAN
• 金额: $ 19.83万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6197175
• 关键词: cell differentiation; ceramides; cytochrome P450; hairless mouse; histogenesis; histology; human tissue; hydroxylation; keratinocyte; membrane biogenesis; membrane lipids; membrane permeability; membrane structure; skin

Epidermal differentiation generates the impermeable stratum corneum (SC), a two-compartment system, composed of lipid-depleted corneocytes and lipid-enriched, extracelluar lamellar membranes. At the interface of these two compartments lies the lipid-bound envelope (LBE), a ceramide-enriched leaflet, that is covalently bound to the outer surface proteins of the cornified envelope. Since omega-hydroxy ceramides re both the predominant lipid constituents of the LBE, and the acylated-omega-OH ceramides are critical components of the extracellular lamellae, these unique lipid species, must be critical for the formation of a competent barrier. However, despite their apparent importance, neither the metabolic pathways leading to omega-OH ceramides, nor the regulation of their generation has been addressed. Moreover, their hypothesized role both in forming the LE and the lamellar membrane structures of the SC remain unresolved. Therefore, we hypothesize that the synthesis of omega-OH ceramides, through the activity of a cytochrome P450 omega-hydroxylase (CYP4A), with the subsequent generation of the lipid-bound envelope and acyl-ceramides, are tightly regulated by epidermal differentiation, permeability barrier requirements, and the program of epidermal barrier development in utero, with members of the nuclear hormone receptor family as the principle regulatory regulators. In this proposal, we will examine whether the generation of the unique epidermal omega-Oh ceramides is critical for formation of both the LBE and the lamellar membranes of the stratum corneum. Specifically, we will address: 1) the regulation of the key enzymatic step (i.e., omega- hydroxylation by epidermal CYP4A) leading to the generation of omega- OH ceramides during epidermal differentiation; 2) the regulation of , and requirement of, omega-OH ceramide synthesis for murine permeability barrier homeostasis; 3) the regulation of, and requirement for, CYP4A and omega-OH ceramide synthesis during fetal barrier ontogenesis; in addition, whether factors that accelerate epidermal barrier development modulate omega-OH ceramide generations; 4) the regulation of omega-hydroxylation and CYP4a expression by members of the nuclear hormone receptor family; and finally, 5) the interaction between the cornified envelope protein(s) and omega-OH ceramides in the formation of the LBE. Since the formation of the LBE, and subsequent generation of the extracellular lamellae, are late steps in epidermal differentiation, the proposed studies should result in significant new information regarding epidermal structure, function, and homeostasis.

表皮分化产生了不透水层角（SC），这是一个由脂质缺失的角膜细胞组成的两室系统和富含脂质的外层层状层状膜。在这两个隔室的界面上，有脂质结合的包膜（LBE），一种富含神经酰胺的传单，共价结合到蜂蜜包膜的外表面蛋白上。由于omega-hydroxy神经酰胺是LBE的主要脂质成分，并且酰化的 - 欧洲糖oH oH神经酰胺是细胞外层层的关键成分，因此这些独特的脂质物种必须至关重要。然而，尽管它们显然很重要，但尚未解决导致欧米茄神经酰胺的代谢途径，也没有解决其代谢途径。此外，它们在形成SC的LE和层状膜结构中的假设作用尚未解决。因此，我们假设通过细胞色素p450 omega-羟化酶（CYP4A）的活性，随后产生脂质结合的包膜和酰基酰胺，通过表皮差异，渗透性范围的核能和型核能构成，并将其范围内的成员紧紧调节激素受体家族作为主要调节剂。在该提案中，我们将研究独特的表皮omega-OH神经酰胺的产生对于形成角质层的LBE和层状膜至关重要。具体而言，我们将解决：1）调节密钥酶促步骤（即通过表皮CYP4A通过表皮CYP4A的omega-羟基化），从而导致表皮分化过程中的omega-oh ceramides产生； 2）Omega-OH神经酰胺合成的调节和需求对鼠渗透性屏障稳态； 3）在胎儿障碍物发生期间，对CYP4A和Omega-OH神经酰胺的合成的调节和需求；此外，加速表皮屏障发育的因素是否会调节omega-oh神经酰胺的世代； 4）核激素受体家族成员对欧米茄羟基化和CYP4A表达的调节；最后，5）在LBE的形成中，蜂蜜的包膜蛋白（S）和omega-OH神经酰胺之间的相互作用。由于LBE的形成以及随后的细胞外层状是表皮分化的较晚步骤，因此拟议的研究应导致有关表皮结构，功能和稳态的重要新信息。