S1P-Mediated Stimulation of Antimicrobial Defense

S1P 介导的抗菌防御刺激

• 批准号: 8852551
• 负责人: YOSHIKAZU UCHIDA
• 金额: $ 33.35万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8852551
• 关键词: Accounting; Address; Antimicrobial Resistance; Apoptosis; Atopic Dermatitis; CCAAT-Enhancer-Binding Protein-alpha; Carrier Proteins; Cell Death; Cell membrane; Cell physiology; Ceramides; Chronic; Clinical; Cutaneous; Defensins; Disease; Distal; Endoplasmic Reticulum; Enzymes; Epidermis; Failure; Generations; Genetic Transcription; Goals; Hemolysin; Infection; Inflammation; Inflammatory; Ligands; Lipids; Mechanics; Mediating; Natural Immunity; Oxidative Stress; Pathogenicity; Pathway interactions; Patients; Permeability; Process; Production; Regulation; Signal Transduction; Skin; Sphingomyelinase; Sphingomyelins; Staphylococcus aureus; Stress; Therapeutic; Time; Up-Regulation; Virulence; Virulence Factors; Virulent; Vitamin D3 Receptor; antimicrobial; antimicrobial peptide; antimicrobial peptide LL-37; base; cathelicidin antimicrobial peptide; endoplasmic reticulum stress; innate immune function; keratinocyte; novel; pathogen; prevent; response; skin disorder; sphingosine 1-phosphate

DESCRIPTION (provided by applicant): Atopic dermatitis (AD) skin displays epidermal permeability as well as antimicrobial deficiency, and is often colonized with virulent S. aureus. Ceramide (Cer) is both an essential permeability barrier lipid species and a bioeffector that alters multiple cellular functions in nucleated epidermal keratinocytes (KC). Importantly, a distal metabolite of Cer, sphingosine-1-phosphate (S1P) also modulates cellular functions, and levels of both Cer and S1P are reduced in AD. Pertinent to this proposal, AD epidermis shows a failure to upregulate a major epidermal cathelicidin antimicrobial peptide (CAMP)/LL-37 expression, which could account for S. aureus colonization and persistence in AD. We recently demonstrated that S1P stimulates CAMP expression not only through the well-characterized vitamin D receptor (VDR)-dependent mechanism, but also by a NF-κB-C/EBPα-dependent pathway that is independent of VDR. Since we also have shown that VDR, but not NF-κB -C/EBPα transactivities, are suppressed in the epidermis under stressed conditions, both mechanisms are likely coordinately regulated to maintain CAMP expression under basal vs. stressed conditions, respectively. We further showed that S. aureus likely subverts S1P-induced upregulation of CAMP by secreting a neutral sphingomyelinase (SMase) (= ß-hemolysin) that preferentially diverts newly-generated Cer to glucosylCer (and sphingomyelin), which we hypothesize would simultaneously diminish S1P production, in parallel with a failure of sustained CAMP uperegulation. Cer and/or S1P could also upregulate ABCA12, a transporter protein that is likely required for CAMP secretion, via PPARß/δ activation. In this proposal, we will investigate 1) the coordinate regulation of CAMP expression/secretion via VDR and NF-κB -C/EBPα mechanisms under basal vs. stressed conditions; 2) how a S. aureus virulence factor subverts the Cer->S1P signaling of CAMP production; and 3) novel, readily- translatable therapeutic approaches that both interdict the S. aureus virulence mechanism and enhance S1P signaling of CAMP production and/or secretion in normal and AD skin.

描述（由适用提供）：特应性皮炎（AD）皮肤显示表皮渗透性以及抗菌缺乏症，并且经常用强烈的金黄色葡萄球菌定植。神经酰胺（CER）既是必不可少的渗透性屏障脂质物种，又是一个生物效应器，可以改变核表皮角质形成细胞（KC）中多个细胞功能。重要的是，有所不同 CER的代谢产物，鞘氨醇1-磷酸（S1P）也可以调节细胞功能，并且AD中CER和S1P的水平均降低。与该提案有关，AD表皮显示未能上调主要表皮cathelicidin抗菌肽（CAMP）/LL-37表达，这可能解释了金黄色葡萄球菌的定殖和AD中的持久性。我们最近证明，S1P不仅通过特征良好的维生素D接收器（VDR）依赖性机制刺激CAMP表达，而且还通过NF-κB-C/EBPα依赖性途径，与VDR无关。由于我们还表明，在压力条件下，在表皮中抑制了VDR而不是NF -κB-C/EBPα的反式活化，因此两种机制可能分别调节以分别调节以在基础和压力条件下维持cAMP的表达。我们进一步表明，金黄色葡萄球菌可能通过分泌中性鞘磷脂酶（SMase）（=ß-毛细蛋白）来颠覆S1P引起的cAMP上调，该鞘磷脂（=ß-Hemolysin）优先将新生成的CER转移到葡萄糖基酯（和鞘磷脂）中，我们简单地将其假设与S1P的生产相比，这将使S1P的生产失败。 CER和/或S1P还可以上调ABCA12，ABCA12是一种通过PPARß/δ激活而可能需要的转运蛋白。在此提案中，我们将研究1）在基本与压力条件下，通过VDR和NF -κB-C/EBPα机制对CAMP表达/分泌的坐标调节； 2）金黄色葡萄球菌病毒因子如何颠覆营地生产的CER-> S1P信号； 3）新颖的，很容易翻译的治疗方法，既限制了金黄色葡萄球菌病毒机制，又增强了正常和AD皮肤中cAMP生产和/或分泌的S1P信号传导。