Role of microRNA in stored RBC induced innate immune suppression

microRNA在储存红细胞诱导的先天免疫抑制中的作用

• 批准号: 9242048
• 负责人: Jennifer Muszynski
• 金额: $ 15.37万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242048
• 关键词: Adult; Aliquot; Area; Attenuated; Basic Science; Bioinformatics; Biology; Biometry; Blood Coagulation Factor VII; Blood Transfusion; Cells; Cessation of life; Child; Clinical; Coculture Techniques; Critical Illness; Critically ill children; Data; Data Set; Development; Erythrocyte Transfusion; Erythrocytes; Experimental Models; Exposure to; Family; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Hour; Immune; Immunobiology; Immunologics; Immunosuppression; Immunosuppressive Agents; Impairment; In Vitro; Inflammatory; Inflammatory Response; Innate Immune Response; Instruction; Intensive Care Units; Knowledge; Laboratories; Link; Lipopolysaccharides; Literature; Mediating; Mediator of activation protein; Medicine; Messenger RNA; Methods; MicroRNAs; Modeling; Molecular Immunology; Movement; Nosocomial Infections; Pathway interactions; Patients; Process; Production; Public Health; Publishing; Research; Research Training; Risk; Role; Safety; Scientist; TNF gene; Techniques; Testing; Time; Training; Transfusion; Translational Research; Untranslated RNA; Work; adverse outcome; aged; base; career; cell type; clinically relevant; cytokine; differential expression; experimental study; health knowledge; improved; improved outcome; innate immune function; insight; member; monocyte; next generation sequencing; novel; overexpression; prevent; public health relevance; solute; translational scientist

 DESCRIPTION (provided by applicant): The candidate's long term goals are to be an independent translational investigator and to improve the safety of blood transfusion by understanding mechanisms of immunosuppressive effects of stored red blood cells (RBCs). The objectives of this proposal are to provide the candidate with early translational research training and to determine the role of microRNA as mediators of red blood cell storage-related innate immune suppression. Innate immune suppression is common in critically ill children and is associated with adverse outcomes. Up to 49% of children who are in the intensive care unit for greater than 48 hours will receive an RBC transfusion. RBC transfusion has been shown to be immunosuppressive through unknown mechanisms. Older stored RBCs suppress innate immune cell (monocyte) function in vitro via heat-stable, soluble mediators capable of interfering with pro-inflammatory cytokine production at the mRNA level. MicroRNA (miRNA) is small, heat- stable, non-coding RNA capable of regulating multiple genes. RBCs contain miRNA and the relative abundance of specific miRNA may change over time during RBC storage. The central hypothesis of this proposal is that stored RBCs suppress monocyte function via the action of specific miRNA. Specific Aim one will comprehensively identify changes in RBC miRNA content over storage duration and determine changes in gene expression in monocytes after exposure to variably aged RBC products. A computational approach will be used to determine miRNA likely responsible for observed immunosuppressive effects of stored RBCs on monocytes. Specific Aim 2 will provide experimental evidence for immunosuppressive effects of specific miRNA. Specific Aim 3 will demonstrate the feasibility of a miRNA- targeted strategy to prevent RBC-induced monocyte suppression. The work described in this submission will lend novel mechanistic insights into RBC transfusion-related innate immune suppression. The conduct of these studies and specific instruction in basic science techniques, molecular immunology, microRNA biology, biostatistics, bioinformatics, and transfusion medicine will support the candidate's transition to independence.

 描述（应用程序提供）：候选人的长期目标是成为独立的转化研究者，并通过了解储存的红细胞（RBC）的免疫抑制作用的机制来提高输血的安全性。该提案的目标是为候选人提供早期的翻译研究培训 并确定microRNA作为红细胞储存相关的先天免疫抑制的介体的作用。先天免疫抑制在重症儿童中很常见，并且与不良后果有关。在重症监护病房中，多达49％的儿童超过48小时将接受RBC输血。通过未知机制，RBC输血已被证明是免疫抑制的。旧存储的RBCS通过热稳定的固体介体在体外抑制先天免疫细胞（单核细胞）功能，能够干扰mRNA水平的促炎性细胞因子的产生。 MicroRNA（miRNA）是小的，热稳定的，非编码的RNA，能够调节多个基因。 RBC含有miRNA，在RBC存储期间，特定miRNA的相对丰度可能会随着时间而变化。该提议的中心假设是，存储的RBC通过特定miRNA的作用抑制单核细胞功能。特定目标将在储存持续时间内全面识别RBC miRNA含量的变化，并确定暴露于变化衰老的RBC产物后单核细胞中基因表达的变化。一种计算方法将用于确定可能导致观察到的RBC对单核细胞的免疫抑制作用的miRNA。特定目标2将为特定miRNA的免疫抑制作用提供实验证据。具体的目标3将证明miRNA靶向策略的可行性，以防止RBC诱导的单核细胞抑制。在此提交中描述的工作将向RBC输血相关的先天免疫抑制提供新的机械洞察力。这些研究和基础科学技术，分子免疫学，microRNA生物学，生物统计学，生物信息学和输血医学中的特定指示的进行将支持候选人向独立的过渡。