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(由申请人提供)：应聘者的长期目标是成为一名独立的翻译研究员，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。这项建议的目标是为应聘者提供早期的翻译研究培训 并确定microRNA作为红细胞储存相关先天免疫抑制的介体的作用。先天性免疫抑制在危重儿童中很常见，并与不良后果有关。在重症监护病房超过48小时的儿童中，高达49%的儿童将接受红细胞输注。红细胞输注通过未知的机制被证明具有免疫抑制作用。在体外，保存较老的红细胞通过热稳定的、可溶的介体抑制天然免疫细胞(单核细胞)的功能，这些介体能够在mRNA水平上干扰促炎细胞因子的产生。MicroRNA(MiRNA)是一种小的、热稳定的、非编码的RNA，能够调节多个基因。红细胞含有miRNA，在红细胞储存过程中，特定miRNA的相对丰度可能会随着时间的推移而变化。这一建议的中心假设是储存的红细胞通过特定的miRNA的作用抑制单核细胞的功能。具体目标一将全面确定RBC miRNA含量随储存时间的变化，并确定暴露于不同老化的RBC产品后单核细胞基因表达的变化。将使用一种计算方法来确定miRNA可能与观察到的储存的红细胞对单核细胞的免疫抑制效应有关。特异性目标2将为特异性miRNA的免疫抑制作用提供实验证据。具体目标3将证明以miRNA为靶点的策略预防RBC诱导的单核细胞抑制的可行性。这份意见书中描述的工作将为与红细胞输注相关的先天免疫抑制提供新的机械学见解。这些研究的开展和在基础科学技术、分子免疫学、微RNA生物学、生物统计学、生物信息学和输血医学方面的具体指导将支持候选人向独立的过渡。