LNCRNA REGULATION OF GENE EXPRESSION & BEHAVIOR

LNCRNA 基因表达调控

• 批准号: 10706509
• 负责人: Sean P Farris
• 金额: $ 55.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706509
• 关键词: Ablation; Acute; Address; Adult; Alcohol consumption; Alternative Splicing; Animal Model; Animals; Astrocytes; Behavior; Biological Models; Biological Process; Brain region; CRISPR screen; CRISPR/Cas technology; Cell physiology; Cells; Central Nervous System; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Data; Development; Disease; Ensure; Environment; Ethanol; Ethanol dependence; Exhibits; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome; Genomic approach; Health; High-Throughput Nucleotide Sequencing; Human; Immune response; In Vitro; Individual; Interferons; Knock-out; Knockout Mice; Knowledge; Length; Literature; LoxP-flanked allele; MALAT1 gene; Mediating; Modernization; Molecular; Morphology; Mus; Mutagenesis; Neurobiology; Neuroglia; Neuroimmune; Neuroimmune system; Neuronal Plasticity; Neurons; Nucleotides; Pathogenesis; Pathologic; Pathway interactions; Pharmacotherapy; Play; Protein Splicing; Proteins; RNA; Regulation; Regulator Genes; Reproducibility; Research Proposals; Role; Stimulus; System; Testing; Tissues; Transcript; Untranslated RNA; alcohol behavior; alcohol effect; alcohol exposure; alcohol sensitivity; alcohol use disorder; behavior test; behavioral phenotyping; cell type; comorbidity; conditional knockout; drinking behavior; genome editing; improved; in vivo; in vivo Model; mammalian genome; nanopore; negative affect; neuroinflammation; neuropsychiatric disorder; novel; rational design; response; single cell sequencing; single-cell RNA sequencing; socioeconomics; transcriptome; transcriptome sequencing

PROJECT SUMMARY Alcohol use disorder (AUD) is a major socioeconomic problem in the modern world. Acute and chronic alcohol exposure is known to lead to system-wide changes in gene expression throughout multiple brain-regions and cell-types. The mammalian genome is comprised of both protein-coding and non-protein-coding transcripts, with less than 2% being protein-coding. Despite outnumbering protein-coding genes, the biological function of most non-coding transcripts remains largely unknown. The largest class of non-coding transcripts are long non-coding RNAs (lncRNAs), which are operationally defined as transcripts longer than 200 nucleotides in length that do not encode for proteins. Most studies conducted to-date for lncRNAs have shown a critical role of lncRNAs in regulation of gene expression. Additionally, lncRNAs are important for alternative splicing of protein-coding transcripts, a biological process necessary for achieving cellular and molecular diversity of proteins. Alternative splicing is crucial for mounting context-dependent responses of the immune system. Chronic alcohol exposure has been previously shown to activate the neuroimmune system, altering CNS plasticity and behavior. Astrocytes are a specialized glial cell-type, outnumbering neurons, and other glial cells in the central nervous system (CNS). Astrocytes contiguously tile the entire CNS, playing a key role in numerous biological functions including responding to CNS insults, activation of neuroimmune pathways, and modulating behavior. Astrocytes are known to be involved in ethanol sensitivity and consumption; however, the contribution of lncRNAs to regulation of neuroimmune pathways in astrocytes and ethanol-related behaviors is unknown. This research proposal will test the overall hypothesis that the expression of lncRNAs in astrocytes is important for coordinating ethanol-induced neuroimmune activation, alternative splicing, and ethanol-related behaviors. Using a combination of in vitro and in vivo approaches this proposal will use advanced genomic approaches to determine the causal relationship of lncRNAs in mediating astrocyte activation and ethanol- related behaviors. Overall, our studies will establish novel molecular mechanisms for regulating gene expression in response to excessive alcohol exposure and contribute to a better understanding of the pathogenesis of AUD.

项目摘要 酒精使用障碍（AUD）是现代社会的一个主要社会经济问题。急性和慢性酒精中毒 已知暴露会导致多个脑区的基因表达发生系统性变化， 细胞类型。哺乳动物基因组由蛋白质编码和非蛋白质编码转录物组成， 只有不到2%是蛋白质编码的。尽管数量超过了蛋白质编码基因， 大多数非编码转录物仍然是未知的。最大的一类非编码转录本是长的 非编码RNA（lncRNA），其在操作上被定义为长于200个核苷酸的转录物， 不编码蛋白质的长度。迄今为止对lncRNA进行的大多数研究都显示了其在肿瘤发生中的关键作用。 lncRNA在基因表达调控中的作用此外，lncRNA对于选择性剪接是重要的。 蛋白质编码转录本，实现细胞和分子多样性所必需的生物学过程， proteins.选择性剪接对于免疫系统的环境依赖性应答至关重要。 长期酒精暴露先前已被证明会激活神经免疫系统，改变中枢神经系统 可塑性和行为。星形胶质细胞是一种特殊的神经胶质细胞类型，数量超过神经元和其他神经胶质细胞 中枢神经系统（CNS）。星形胶质细胞连续地覆盖整个中枢神经系统，在神经系统的功能中起着关键作用。 许多生物学功能，包括对CNS损伤的反应、神经免疫途径的激活，以及 调节行为已知星形胶质细胞参与乙醇敏感性和消耗;然而， lncRNA对星形胶质细胞中神经免疫通路的调节和乙醇相关行为的贡献是 未知这项研究计划将测试整体假设，即星形胶质细胞中lncRNA的表达 对于协调乙醇诱导的神经免疫激活、选择性剪接和乙醇相关的 行为。使用体外和体内方法的组合，该提议将使用先进的基因组技术， 确定lncRNA介导星形胶质细胞活化和乙醇的因果关系的方法- 相关行为。总的来说，我们的研究将建立新的调控基因的分子机制， 表达，并有助于更好地了解 AUD的发病机制