miRNA-mediated regulation of LPS tolerance

miRNA 介导的 LPS 耐受性调节

基本信息

批准号：
8987945
负责人：
Sankar Ghosh
金额：
$ 24万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/8987945
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 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 genome-wide in vivo interest macrophage microbial mortality novel novel therapeutics overexpression prevent promoter public health relevance response septic transcription factor transcriptome sequencing

项目摘要

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（由申请人提供）：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，同时限制炎症细胞因子的过度产生会导致感染引发的全身炎症状况（脓毒症）的进展，巨噬细胞对脂多糖等促炎剂的长期治疗产生耐受性，这可能是针对这种有害结果的保护性反应。耐受性巨噬细胞在再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。然而，这种现象的分子基础是。不同的机制可以导致在耐受性诱导等过程中看到的选择性基因表达，特别是，迄今为止，还没有 miRNA 成为选择性基因表达的重要转录后调节因子。已发现其选择性地影响转录，从而概括了 LPS 耐受期间注意到的基因表达变化。然而，我们已经鉴定出许多 miRNA 种类，这些 miRNA 种类在长期暴露于 LPS 处理后在巨噬细胞中表达，并且似乎选择性地调节 LPS 耐受过程中的基因表达变化。 miR-222 是我们筛选中鉴定的最高表达的 miRNA，我们的初步结果表明 miR-222 靶向巨噬细胞中 SWI/SNF 重塑复合物的 Brg1 亚基。炎症细胞因子子集的产生减弱；然而，鉴于 miR-222 表达的动力学以及新定义的 miR-222，它使 TLR4 信号保持完整。靶标 Brg1 已被证明在 LPS 耐受过程中介导选择性启动子处的染色质重塑，我们发现 miR-222 可能是真正的耐受调节剂，我们计划利用基因组分析和新的遗传模型来验证 miR 的作用。 -222 作为耐受性调节剂，该项目对于设计在脓毒症进展过程中急性诱导耐受性和对抗炎症的疗法具有令人兴奋的意义。