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（由适用提供）：炎症反应来自精心平衡的基因表达模式，旨在控制微生物感染，同时限制损害感染。炎症细胞因子的过度产生有助于感染触发的全身性炎症状况败血症的进展。在可能对这种有害结果的受保护反应中，巨噬细胞变得容忍了促炎剂（如脂多糖（LPS））的长时间治疗。耐受性巨噬细胞减少促炎性细胞因子的产生，而在重新刺激后支持抗炎和抗菌基因。但是，这种现象的分子基础尚未明确定义。各种机制可以导致在过程中看到的选择性基因表达，例如耐受性的诱导。特别是microRNA（miRNA），已经成为选择性基因表达的重要后调节剂。远处没有发现miRNA以概括LPS耐受性期间基因表达变化的方式选择性影响转录。但是，我们已经确定了许多miRNA物种在长期暴露于LPS治疗后在巨噬细胞中表达，并且似乎选择性地调节了与炎症相关基因的表达。 miR-222是在我们屏幕上鉴定出的miRNA中最高表达的，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。这种靶向导致炎症细胞因子的一部分的产生。但是，它使TLR4信号完整。鉴于miR-222表达的动力学以及新定义的miR-222靶标BRG1的事实已显示出在LPS耐受性过程中选择性启动子对中值染色质重塑，我们假设miR-222可能是可耐受性的真正调节剂。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作为耐受性的调节剂的作用。该项目对治疗学的设计具有令人兴奋的含义，以急剧诱导脓毒症进展过程中的耐受性和作战注射。