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/摘要皮肤最外层（即角质层 (SC)）富含脂质的细胞外层膜，可促进表皮渗透性屏障功能，这是哺乳动物在干燥环境中生存所需的。 10 种神经酰胺 (Cer) 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%。形成层状膜结构不仅需要它们的数量，而且需要它们的分子异质性。特别是，w-O-acylCer（或 acylCer），含有酯化至酰胺连接的超长链脂肪酸（> C28）的 w-羟基末端的酰基，不仅是表皮所独有的，而且对于正常的渗透性屏障稳态也至关重要。重要的是，特应性皮炎 (AD) 中会出现选择性的 acylCer 缺乏，这可能会进一步加剧 SC 结构的固有缺陷。我们发现，抑制β-羟基化会降低酰基Cer的产生，引发屏障异常，并且缺乏正常FA延伸酶、极长链FA（或ELOVL）4延伸的小鼠表现出致命的产后屏障缺陷；在这些小鼠中，与角质化包膜蛋白（角质细胞脂质包膜，CLE）共价连接的 acylCer 和 w-OH Cer 均未形成。这些酰基Cer对于细胞外层状膜组织和角质细胞脂质包膜形成至关重要。我们最近表明，酰基辅酶A蜡醇酰基转移酶（AWAT）1和CGI-58（三酰甘油脂肪酶的辅因子）都是w-O-酯化所必需的，从而导致酰基Cer的产生。然而，无论是 AD 中 acylCer 缺乏的基础，还是 acylCer 缺乏对 AD 发病机制的贡献，均未知。我们假设 AD 中发生了 acylCer 的合成减少或水解加速。这种生化异常可归因于 T 辅助细胞 2 (Th2) 细胞因子诱导的下调和/或分别通过外部湿度和渗透传感器 TRPV4 和 TonEBP 产生的异常干旱应激介导的 acylCer 信号传导。这些信号传导缺陷共同导致了 AD 中 acylCer 的缺乏。我们将研究 1) acylCer 缺乏的酶（关键酶/辅因子，即 ELOVL4、w-羟化酶、AWAT1 和 CGI​​-58）基础以及 AD 中 acylCer 缺乏的结构/功能后果； 2) Th2细胞因子如何下调AD中的acylCer； 3) 干旱胁迫如何通过 TRPV4 受体和/或 TonEBP 信号传导调节 acylCer 合成及其在 AD 中的变化； 4) AD 中 acylCer 恢复的新治疗策略。