P3: ROLE OF MIRNAS IN DENGUE IMMUNOPATHOGENESIS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 登革热是人类最常见的蚊媒病毒疾病。登革出血热(DHF)和登革休克综合征(DSS)是严重登革病毒(DENV)感染的两种危及生命的形式，表现为血管通透性增加和血浆渗漏。现有证据表明，人单核/巨噬细胞感染后，炎性细胞因子和其他免疫介质的产生显著增加，作用于血管内皮细胞，导致内皮通透性改变。然而，这种细胞反应是如何调节的，以及这种调节如何有助于DHF/DSS发病机制的独特特征，目前尚不清楚。最近的研究表明，microRNAs(MiRNAs)是一类小的非编码调控RNA，在大多数细胞和发育过程中发挥着重要的作用，miRNA表达的失控与许多人类疾病有关。这项研究的中心假设是miRNAs可能是调节人单核/巨噬细胞和血管内皮细胞在DENV感染中的细胞反应的基本因素。为了解决这一问题，将对DENV感染的单核/巨噬细胞和血管内皮细胞以及用感染的单核/巨噬细胞释放的免疫介质处理的血管内皮细胞进行miRNA表达谱分析。MiRNAs在DHF和DSS致病过程中的调节作用将进一步表征。这项研究的结果将有助于阐明DENV感染中的关键细胞反应，并为DHF免疫发病的分子机制提供有价值的见解。这些发现可能会发现预防和可能治疗DHF/DSS的新策略。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Dengue is the most prevalent mosquito-borne viral disease in humans. Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), the life-threatening forms of severe dengue virus (DENV) infection, are manifested by increased vascular permeability and plasma leakage. Available evidence indicates that infection of human monocytes/macrophages results in a dramatic increase in production of inflammatory cytokines and other immune mediators, which act on vascular endothelium and cause alteration of endothelial permeability. However, how such cellular responses are regulated and how such regulations contribute to the unique feature of DHF/DSS pathogenesis are unclear. Recently, it was demonstrated that microRNAs (miRNAs), a class of small non-coding regulatory RNAs, play important roles in most cellular and developmental processes, and deregulation of miRNA expression is associated with many human diseases. The central hypothesis of this study is that miRNAs may serve as the essential factors that modulate cellular responses of human monocytes/macrophages and vascular endothelial cells in DENV infection. To address this, miRNA expression profiling in DENV-infected monocytes/macrophages and vascular endothelial cells, and vascular endothelial cells that are treated with the immune mediators released from infected monocytes/macrophages, will be performed and analyzed. Regulatory roles of miRNAs in the pathogenic process of DHF and DSS will be further characterized. The findings from this study will help to clarify critical cellular responses in DENV infection, and provide valuable insights into the molecular mechanism of DHF immunopathogenesis. Such findings may uncover new strategies for the prevention and possibly treatment of DHF/DSS.