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: 8196327
• 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/8196327
• 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. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE: It is increasingly accepted that a primary barrier defect underlies atopic dermatitis (AD), which displays selective acylceramide (acylCer) deficiency, resulting in increased transcutaneous exposure to allergens which induce AD, and stimulate progression of AD to asthma and allergic rhinitis. The insights gained from the proposed studies will identify novel forms of therapy for AD, a common disease in veterans, based upon normalizing acylCer levels using appropriate metabolic precursors or stimulation of endogenous acylCer production.

描述（由申请人提供）：