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Functional characterization of an enhancer RNA in cerebral ischemia

增强子 RNA 在脑缺血中的功能表征

基本信息

批准号：
10679009
负责人：
Ashutosh Dharap
金额：
$ 37.38万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-25 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679009
关键词：
Acetylation Acute Adult Affect Binding Binding Sites Biological Biological Assay Brain Brain Injuries Budgets Cell Adhesion Cell Cycle Arrest Cell Death Cerebral Ischemia Cerebral cortex ChIP-seq Chromatin Cyclic AMP DNA DNA Polymerase II Data Development Disease Enhancers Estrogens Extracellular Matrix Female Fluorescent in Situ Hybridization Functional disorder Future Gene Expression Gene Expression Regulation Gene Proteins Genes Genetic Enhancer Element Genetic Transcription Genomics Histones Immunoprecipitation Infarction Investigation Ischemia Ischemic Stroke Lysine Macrophage Maps Mediating Methods Middle Cerebral Artery Occlusion Molecular Molecular Target Mus Neurologic Neurons Outcome Pathologic Pathway interactions Phase Phenotype Physiological Play Proteins RNA Regulator Genes Reperfusion Therapy Reporter Reporting Role Running Sensorimotor functions Signal Transduction Stimulus Stroke Structure TP53 gene Testing Therapeutic Time Transcript Transcriptional Activation Translations Ubiquitination Untranslated RNA Western Blotting Work blood-brain barrier disruption cdc Genes cell cortex cell type crosslink endoplasmic reticulum stress experimental study gene repression genome-wide genomic locus improved in vivo knock-down loss of function male new therapeutic target novel post stroke programs response sex stroke outcome transcription factor transcriptome sequencing virtual

项目摘要

Recent studies have reported widespread transcription of mammalian enhancers into noncoding RNA transcripts in a stimulus-dependent manner. Growing evidence shows that these enhancer RNAs (eRNAs) have essential roles in orchestrating higher-order chromatin interactions to facilitate gene expression and phenotypic outcomes during development and disease. As a result, eRNAs are emerging as an important component of the gene regulatory machinery. Due to their very recent discovery, the expression and roles of eRNAs in stroke is virtually unknown. Recently, we applied a combination of genome-wide RNA-seq and genome-wide enhancer mapping using ChIP-seq to identify a number of stroke-induced eRNAs at multiple time-points of reperfusion in the mouse cerebral cortex. Our preliminary data confirmed enhancer activity of the genomic loci encoding the eRNAs, showed that the eRNAs are localized to the chromatin, and revealed an important role for one such eRNA in modulating post-stroke brain damage and gene expression. The molecular interactions, functional mechanisms and sex-dependent effects of eRNAs on the post-stroke pathophysiology are unexplored. In the current project, we build upon our preliminary data to evaluate eRNA functionality in-depth during stroke in the adult mouse cortex. Specific Aim 1 will use a combination of crosslinking-immunoprecipitation, fluorescence in situ hybridization and transcriptional-state analysis to determine the molecular targets of the eRNAs as a function of post-stroke reperfusion time in the mouse cortex. Specific Aim 2 will employ eRNA loss-of-function in vivo followed by cellular, physiological, pathological and neurological analyses to evaluate the role of the eRNA in propagating the post-stroke pathophysiology. Specific Aim 3 will evaluate the molecular targets and pathophysiological effects of the eRNA in the female mouse cortex. Together, this work will illuminate the significance of eRNAs in the cerebral cortex and may reveal novel gene regulatory relationships in stroke. This work will pave the way for future studies exploring the therapeutic manipulation of eRNAs to improve post-stroke outcomes.

最近的研究报道了哺乳动物增强子广泛转录为非编码RNA