MicroRNAs in atopic dermatitis pathogenesis: a role for mast cell and sphingosine-1-phosphate?

MicroRNA 在特应性皮炎发病机制中：肥大细胞和 1-磷酸鞘氨醇的作用？

• 批准号: 9035633
• 负责人: CAROLE A OSKERITZIAN
• 金额: $ 17.62万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9035633
• 关键词: Acute; Adult; Adverse effects; Affect; Affinity; Allergens; Allergic; Allergic Reaction; Antigens; Atopic Dermatitis; Automobile Driving; Binding; Biological Process; Blood Vessels; CCL19 gene; Cell physiology; Cells; Cellular biology; Child; Chronic Disease; Clinical; Cues; Data; Development; Disease; Down-Regulation; Eczema; Enzymes; Epigenetic Process; Event; Exposure to; Gene Expression; Gene Targeting; High Prevalence; Human; IgE; IgE Receptors; Immune; Immunoglobulin Isotypes; Immunosuppressive Agents; Infiltration; Inflammation; Inflammatory; Leukocytes; Link; Mediating; Mediator of activation protein; Medical; Messenger RNA; MicroRNAs; Microarray Analysis; Molecular; Molecular Target; Mus; Ovalbumin; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Pre-Clinical Model; Prevalence; Preventive; Process; Production; Prophylactic treatment; Pruritus; Quality of life; RANTES; RNA Interference; Regulation; Reporting; Role; SPHK1 enzyme; Sampling; Signal Pathway; Site; Skin; Sphingolipids; Stat3 protein; T-Lymphocyte; Transcriptional Activation; Triad Acrylic Resin; Untranslated RNA; Up-Regulation; allergic response; base; chemokine; chronic inflammatory skin; clinical efficacy; crosslink; cytokine; disability burden; epigenetic regulation; genome-wide; innovation; insight; lipid mediator; mast cell; mouse model; novel; outcome forecast; prevent; protein expression; public health relevance; sensitizing antigen; skin disorder; skin lesion; spatiotemporal; sphingosine 1-phosphate; transcription factor

 DESCRIPTION (provided by applicant) Atopic dermatitis (AD), also called eczema, is characterized by allergic skin inflammation with remodeling and accumulation of immune cells, including T cells and mast cells (MC), but its pathogenesis remains poorly understood. Recalcitrant itching is most common and associated with poor quality of life for AD patients. Rising world-wide prevalence has been reported among children and adults, affecting at least 15% and 2-10% of each population, respectively. The high burden of disability related to eczema remains unfortunately consistent. In many AD cases, insufficient eczema relief and lack of clinical efficacy of current topical treatments, associated with deleterious side effects of immunosuppressive drugs have triggered many ongoing treatment studies, emphasizing the unmet medical need for better pharmacological options in AD. Because of its inflammatory components requiring the coordinated actions of diverse molecular pathways, we reasoned that microRNAs, small non coding RNAs recently recognized as potent epigenetic regulators of disease processes through mRNA targeting, could exert important functions in the spatiotemporal control of gene and protein expression observed during the development of AD. Little is known pertaining to such epigenetic changes occurring in AD. In addition, even though 80% of AD patients display high levels of circulating immunoglobulin (Ig) E, the Ig isotype detected in allergic patients, the allergic component of AD remains controversial. Located around blood vessels, skin-resident MC are key effectors of allergic reactions, increased in number in AD skin lesions of humans and mice. We have discovered that crosslinking of MC expressed high affinity receptors for IgE (FcεRI) by allergen triggers MC activation, subsequent release of chemokines linked to Stat3 transcription factor and activation of sphingosine kinase 1 (SphK1), the enzyme that produces sphingosine-1-phosphate (S1P), a potent inflammatory and chemotactic lipid mediator. Using a well-established AD-like mouse model, we have identified a set of three miRNAs consistently downregulated in inflamed skins which leads to the up-regulation of many target genes involved in MC biology and immune cell recruitment. The objectives of this application are: to establish the miRNA profiling at the onset of AD and its association with MC functions; to elucidate the signaling pathways controlled by the miRNA triad and their relevance to S1P and chemokine production and MC activation. We anticipate our proposed studies will provide evidence for the importance of epigenetics in the regulation of AD initiation involving MC and S1P contributions to inflammatory cell recruitment through Stat3-mediated chemokine production, hence leading to AD progression. We are proposing these mechanistic insights will identify new molecular targets to prevent AD.

 描述（申请人提供） 特应性皮炎（AD），也称为湿疹，其特征是过敏性皮肤炎症，伴有免疫细胞（包括 T 细胞和肥大细胞（MC））的重塑和积累，但其发病机制仍知之甚少。据报道，这种疾病在儿童和成人中最为常见，并且与 AD 患者的生活质量差有关，分别影响至少 15% 和 2-10% 的人群。不幸的是，在许多 AD 病例中，与湿疹相关的残疾负担仍然存在，湿疹缓解不足和当前局部治疗缺乏临床疗效，以及免疫抑制药物的有害副作用引发了许多正在进行的治疗研究，强调了对更好的治疗需求未得到满足。由于 AD 的炎症成分需要不同分子途径的协调作用，我们推测 microRNA（最近被认为通过 mRNA 靶向的疾病过程的有效表观遗传调节剂）可以发挥重要功能。 AD 发展过程中观察到的基因和蛋白质表达的时空控制，对于 AD 中发生的这种表观遗传变化知之甚少。此外，尽管 80% 的 AD 患者表现出高水平的循环免疫球蛋白 (Ig) E，即 Ig。在过敏患者中检测到的同种型，AD 的过敏成分仍然存在争议，皮肤驻留的 MC 是过敏反应的关键效应物，我们发现 MC 的交联在人类和小鼠的 AD 皮肤损伤中数量增加。过敏原表达 IgE (FcεRI) 高亲和力受体，触发 MC 激活，随后释放与 Stat3 转录因子相关的趋化因子，并激活鞘氨醇激酶 1 (SphK1)，该酶产生 1-磷酸鞘氨醇 (S1P)，一种强效炎症因子使用成熟的 AD 样小鼠模型，我们鉴定了一组在炎症中持续下调的 miRNA。该应用的目的是：建立 AD 发病时的 miRNA 分析及其与 MC 功能的关联，以阐明信号通路。我们预计我们提出的研究将为表观遗传学在 AD 起始调节中的重要性提供证据，其中涉及 MC 和 S1P 通过炎症细胞募集的贡献。 Stat3 介导的趋化因子产生，从而导致 AD 进展，我们提出这些机制见解将确定预防 AD 的新分子靶点。