S1P-Mediated Stimulation of Antimicrobial Defense

S1P 介导的抗菌防御刺激

基本信息

批准号：
8507601
负责人：
YOSHIKAZU UCHIDA
金额：
$ 31.68万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507601
关键词：
ATP-Binding Cassette Transporters Abbreviations Accounting Address Antimicrobial Resistance Apoptosis Atopic Dermatitis CCAAT-Enhancer-Binding Proteins Carrier Proteins Cell Death Cell membrane Cell physiology Ceramides Chronic Clinical Cutaneous Defensins Disease Distal Drug resistance 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 enhancer binding protein innate immune function keratinocyte novel pathogen prevent response skin disorder sphingosine 1-phosphate

项目摘要

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-?B-C/EBP¿-dependent pathway that is independent of VDR. Since we also have shown that VDR, but not NF- ?B -C/EBP¿ 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) (= ¿-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 PPAR¿/¿ activation. In this proposal, we will investigate 1) the coordinate regulation of CAMP expression/secretion via VDR and NF- ?B -C/EBP¿ 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（由申请人提供）：特应性皮炎 (AD) 皮肤表现出表皮通透性和抗菌缺陷，并且经常定植有剧毒的金黄色葡萄球菌 (Cer)，它既是一种重要的通透性屏障脂质种类，又是一种改变多种因素的生物效应器。有核表皮角质形成细胞（KC）的细胞功能重要的是，远端。 Cer 的代谢物 1-磷酸鞘氨醇 (S1P) 也可调节细胞功能，并且 AD 中 Cer 和 S1P 的水平均降低。与该提议相关，AD 表皮未能上调主要的表皮抗菌肽 (CAMP)。 /LL-37 表达，这可以解释金黄色葡萄球菌在 AD 中的定殖和持续存在。我们最近证明 S1P 不仅刺激 CAMP 表达。通过充分表征的维生素 D 受体 (VDR) 依赖性机制，还通过 NF-?B-C/EBP¿ -依赖于VDR的途径，因为我们也已经证明了VDR，但不是NF-?B-C/EBP¿反式活性在应激条件下在表皮中受到抑制，这两种机制可能分别在基础条件和应激条件下协调调节以维持 CAMP 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来破坏 S1P 诱导的 CAMP 上调。 (SMase) (= ¿-溶血素) 优先将新生成的 Cer 转化为葡萄糖基 Cer（并且我们参与的神经鞘磷脂）会同时减少 S1P 的产生，同时 CAMP Cer 和/或 S1P 持续上调的失败也可能通过 PPAR 上调 ABCA12（一种可能是 CAMP 分泌所需的转运蛋白）。 /¿在本提案中，我们将研究 1) 通过 VDR 和 NF-B-C/EBP 协调调节 CAMP 表达/分泌。基础与应激条件下的机制；2) 金黄色葡萄球菌毒力因子如何破坏 CAMP 产生的 Cer->S1P 信号传导；以及 3) 既阻断金黄色葡萄球菌毒力机制又增强 S1P 的新型、易于转化的治疗方法。正常和 AD 皮肤中 CAMP 产生和/或分泌的信号传导。