miRNA-mediated regulation of LPS tolerance

miRNA 介导的 LPS 耐受性调节

• 批准号: 9058465
• 负责人: Sankar Ghosh
• 金额: $ 20万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9058465
• 关键词: Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Binding Sites; Cells; Complex; Dependence; Disease Progression; Dose; Equilibrium; Experimental Models; Exposure to; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Models; Genetic Transcription; Genomics; Health; Infection; Inflammation; Inflammatory; Inflammatory Response; Kinetics; Knockout Mice; Lead; Lipopolysaccharides; Mediating; Methods; MicroRNAs; Modeling; Molecular; Monitor; Mus; Outcome; Play; Process; Production; Regulation; Role; Sepsis; Septic Shock; Signal Transduction; TLR4 gene; Therapeutic; Time; Transcript; United States; antimicrobial; base; chromatin remodeling; clinically relevant; combat; cytokine; design; genetic signature; genome-wide; in vivo; interest; macrophage; microbial; mortality; novel; novel therapeutics; overexpression; prevent; promoter; response; septic; transcription factor; transcriptome; transcriptome sequencing

 DESCRIPTION (provided by applicant): The inflammatory response results from a carefully balanced pattern of gene expression that is designed to control microbial infection, while limiting damaging inflammation. Excessive production of inflammatory cytokines contributes to the progression of the infection-triggered systemic inflammatory condition, sepsis. In what may be a protective response against this deleterious outcome, macrophages become tolerant to prolonged treatment with pro-inflammatory agents such as lipopolysaccharide (LPS). Tolerant macrophages reduce production of pro-inflammatory cytokines in favor of anti- inflammatory and anti-microbial genes upon re-stimulation. However, the molecular basis of this phenomenon is not clearly defined. Diverse mechanisms can lead to the selective gene expression seen during processes such as the induction of tolerance. MicroRNAs (miRNAs), in particular, have emerged as important post-transcriptional regulators of selective gene expression. Thus far, no miRNA has been found to selectively affect transcription in a way that recapitulates the gene expression changes noted during LPS tolerance. However, we have identified a number of miRNA species that are expressed in macrophages after prolonged exposure to LPS treatment and which appear to selectively modulate the expression of inflammation-related genes. miR-222 was the most highly expressed of the miRNAs identified in our screen, and our preliminary results suggest that miR-222 targets the Brg1 subunit of the SWI/SNF remodeling complex in macrophages. This targeting leads to attenuated production of a subset of inflammatory cytokines; however, it leaves TLR4 signaling intact. Given the kinetics of miR-222 expression, and the fact that the newly defined miR-222 target, Brg1, has been shown to mediate chromatin remodeling at selective promoters during LPS tolerization, we hypothesize that miR-222 may be a bona fide regulator of tolerance. We plan to utilize genomic analysis and a novel genetic model to validate the role of miR-222 as a regulator of tolerance. This project has exciting implications for the design of therapeutics to acutely induce tolerance and combat inflammation during sepsis progression.

 描述(申请人提供)：炎症反应是由精心平衡的基因表达模式引起的，该模式旨在控制微生物感染，同时限制 破坏性炎症。炎症细胞因子的过度产生有助于感染引发的全身炎症状态的进展，即脓毒症。巨噬细胞对这种有害结果可能是一种保护性反应，可以耐受脂多糖(LPS)等促炎剂的长期治疗。耐受巨噬细胞在再次刺激时减少促炎细胞因子的产生，有利于抗炎和抗微生物基因的产生。然而，这种现象的分子基础还没有明确的定义。不同的机制可以导致在诱导耐受等过程中看到的选择性基因表达。尤其是microRNAs(MiRNAs)，已经成为选择性基因表达的重要转录后调节因子。到目前为止，还没有发现miRNA选择性地影响转录，这种方式概括了在脂多糖耐受过程中注意到的基因表达变化。然而，我们已经确定了一些在巨噬细胞中长时间暴露于内毒素治疗后表达的miRNA物种，它们似乎选择性地调节炎症相关基因的表达。MiR-222是我们筛选到的miRNAs中表达最高的，我们的初步结果表明miR-222针对巨噬细胞中SWI/SNF重塑复合体的BRG1亚单位。这种靶向导致炎性细胞因子子集的产生减弱；然而，它保持了TLR4信号的完整。鉴于miR-222的表达动力学，以及新定义的miR-222靶标BRG1已被证明在脂多糖耐受过程中介导选择性启动子的染色质重塑，我们假设miR-222可能是一个真正的耐受调节因子。我们计划利用基因组分析和一种新的遗传模型来验证miR-222作为耐受调节因子的作用。该项目对在脓毒症进展过程中急性诱导耐受和抗炎的治疗方法的设计具有令人兴奋的意义。