Regulation/Role of AcylCer in Normal Epidermis and Atopic Dermatitis

AcylCer 在正常表皮和特应性皮炎中的调节/作用

• 批准号: 8391561
• 负责人: Peter M Elias
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391561
• 关键词: Accounting; Acute; Acyl Coenzyme A; Acyltransferase; Address; Adult; Affect; Air; Alcohols; Alleles; Allergens; Allergic rhinitis; Amides; Animals; Asthma; Atopic Dermatitis; Binding; Biochemical; Birth; Bypass; CD4 Positive T Lymphocytes; Ceramides; Chemicals; Childhood; Clinical; Coenzymes; Coupled; Data; Defect; Dermatologist; Development; Disease; Down-Regulation; Eczema; Environment; Enzymes; Epidermis; Esterification; Exposure to; Extracellular Domain; Extracellular Matrix; Extracellular Space; Face; Failure; Family; Flare; Funding; Generations; Genes; Haptens; Heating; Helper-Inducer T-Lymphocyte; Heterogeneity; Homeostasis; Human; Humidity; Hydration status; Hydrolysis; Hydroxylation; Ichthyosis Vulgaris; Immune; Individual; Inflammation; Inherited; Interleukin-4; Irritants; Kininogenase; Knock-in Mouse; LXRalpha protein; Lead; Ligands; Link; Lipase; Lipid Binding; Lipids; Liver; Mechanics; Mediating; Membrane; Metabolic; Metabolism; Mixed Function Oxygenases; Modeling; Molecular; Mus; Mutation; Neonatal; Nuclear Hormone Receptors; Occupational Dermatitis; PPAR alpha; PPAR-beta; Pathogenesis; Patients; Permeability; Peroxisome Proliferator-Activated Receptors; Phenotype; Pilot Projects; Positioning Attribute; Prevalence; Production; Pump; Regulation; Reporting; Research; Role; Serine; Serine Protease; Serine Proteinase Inhibitors; Signal Transduction; Skin; Stratum corneum; Stress; Structural Protein; Structure; Surface; Syndrome; Tail; Tissues; Transgenes; United States National Institutes of Health; Up-Regulation; Vanilloid; Very Long Chain Fatty Acid; Veterans; Water; Waxes; Weight; abstracting; acyl group; alveolar lamellar body; base; cofactor; cohesion; cytokine; enhancer binding protein; env Gene Products; extracellular; filaggrin; improved; insight; kallikrein 4; keratinocyte; keratinocyte differentiation; lipid metabolism; liver function; loss of function mutation; mRNA Expression; microbial; monolayer; mouse model; novel; novel strategies; novel therapeutics; overexpression; pathogen; prevent; public health relevance; receptor; response; restoration; sensor; skin disorder; stressor; surfactant; uptake

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Lipid-enriched extracellular lamellar membranes in the outermost layer of skin, i.e., stratum corneum (SC), subserve epidermal permeability barrier function, as required for mammalian survival in a dry environment. A family of 10 ceramides (Cer) dominates in these membranes, accounting for about H50% of SC lipid, and therefore H5% of the total weight of SC. Not only their quantities, but also their molecular heterogeneity is required to form lamellar membrane structures. In particular, w-O-acylCer (or acylCer), that contains an acyl group esterified to the w-hydroxy terminal of amide-linked very long-chain fatty acids (>C28), is not only unique to the epidermis, but also critical for normal permeability barrier homeostasis. Importantly, a selective deficiency in acylCer occurs in atopic dermatitis (AD), which could further aggravate inherent defects in SC structures. We showed that inhibition of w-hydroxylation decreases acylCer production, provoking barrier abnormalities, and that mice lacking the normal FA elongase, elongation of very long chain FA (or ELOVL) 4, display a lethal post-natal barrier defect; neither acylCer nor the w-OH Cer covalently-attached to cornified envelope proteins (corneocyte lipid envelope, CLE) are formed in these mice. These acylCer are essential for both extracellular lamellar membrane organization, and for corneocyte lipid envelope formation. We recently showed that both acyl-CoA wax alcohol acyltransferases (AWAT) 1 and CGI-58 (a cofactor of triacylglycerol lipase) are further required for w-O-esterification, leading to acylCer production. Yet, neither the basis for acylCer deficiency in AD, nor the contribution of acylCer deficiency to the pathogenesis of AD is known. We hypothesize that either decreased synthesis or accelerated hydrolysis of acylCer occurs in AD. This biochemical abnormality can be attributed to increased T helper cell 2 (Th2) cytokine-induced downregulation and/or aberrant xeric stress-mediated-signaling of acylCer production via the external humidity and osmotic sensors, TRPV4 and TonEBP, respectively. Together, these signaling defects account for deficiency of acylCer in AD. We will investigate 1) the enzymatic (key enzymes/cofactor, i.e., ELOVL4, w-hydroxylase, AWAT1, and CGI-58) basis for acylCer deficiency as well as the structural/functional consequences of acylCer deficiency in AD; 2) how Th2 cytokines downregulate acylCer in AD; 3) how xeric stress regulates acylCer synthesis via the TRPV4 receptor and/or TonEBP signaling and their alterations in AD; and 4) novel therapeutic strategies for acylCer restoration in AD.

描述（由申请人提供）： 项目摘要/富含脂质的脂质外层状膜，即皮肤最外层的层，即角质层（SC），在干燥环境中所需的哺乳动物生存所必需的表皮渗透性屏障功能。一个10个神经酰胺（CER）的家族在这些膜中占主导地位，约占SC脂质的H50％，因此占SC总重量的H5％。不仅需要它们的数量，而且还需要它们的分子异质性才能形成层状膜结构。特别是，含有酰胺链的W-acylcer（或酰基），该酰基酯酯化为酰胺连接的非常长链脂肪酸（> c28）的W-羟基末端，不仅是表皮所特有的，而且对正常的持续性屏障稳态也是至关重要的。重要的是，在特应性皮炎（AD）中会出现选择性缺陷，这可能会进一步加剧SC结构中固有的缺陷。我们表明，抑制W-羟基化会降低酰基的产生，引发屏障异常，并且缺乏正常FA延伸酶的小鼠，长长的链条FA（或Elovl）4，表现出致命的产后屏障缺陷；在这些小鼠中，酰基蛋白（角膜细胞脂质包膜，CLE）均未共价连接到糖化的包膜蛋白（角膜细胞脂质包膜）。这些酰基人对于细胞外层状膜组织和角膜脂质包膜的形成至关重要。我们最近表明，W-O-酯化进一步需要酰基铜蜡醇酰基转移酶（AWAT）1和CGI-58（三酰甘油脂肪酶的辅助因子）才能用于W-O酯化，从而导致酰基蛋白酶的产生。然而，既不知道AD酰基人缺乏症的基础，也不知道酰基人缺乏对AD发病机理的贡献。我们假设在AD中发生合成降低或酰基水解的加速水解。这种生化异常可以归因于T辅助细胞2（Th2）细胞因子诱导的下调和/或异常的Xeric Xeric应激介导的酰基介导的酰基介导的酰基通过外部湿度和渗透传感器的信号，分别是TRPV4和TONEBP。总之，这些信号传导缺陷解释了AD中酰基人的缺乏。我们将研究1）酶促缺乏症的酶（即酶/辅因子，即Elovl4，W-Hydroxylase，AWAT1和CGI-58）的基础，以及AD中酰基人缺乏的结构/功能后果； 2）Th2细胞因子如何在AD中下调酰基； 3）Xeric应力如何通过TRPV4受体和/或TONEBP信号传导及其在AD中的改变来调节酰基来的合成； 4）AD中酰基恢复的新型治疗策略。