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）是现代世界中的主要社会经济问题。急性酒精 已知暴露会导致整个多个大脑区域的基因表达变化，并且 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本组成， 不到2％是蛋白质编码。尽管人数超过蛋白质编码基因，但 大多数非编码成绩单仍然在很大程度上未知。最大的非编码成绩单很长 非编码RNA（LNCRNA），在操作上定义为转录本长于200个核苷酸 不为蛋白质编码的长度。大多数针对LNCRNA进行迄今为止的研究表现出至关重要的作用 LNCRNA在基因表达调节中的。此外，lncrnas对于替代剪接很重要 蛋白质编码转录本，这是实现细胞和分子多样性所必需的生物学过程 蛋白质。替代剪接对于安装免疫系统的上下文响应至关重要。 先前已显示出慢性酒精暴露会激活神经免疫系统，改变了CNS 可塑性和行为。星形胶质细胞是一种专业的神经胶质细胞类型，人数超过神经元和其他神经胶质细胞 在中枢神经系统（CNS）中。星形胶质细胞连续瓷砖整个中枢神经系统，在 许多生物学功能，包括应对中枢神经系统的侮辱，神经免疫途径的激活和 调节行为。已知星形胶质细胞参与乙醇的敏感性和消耗；但是， LNCRNA对星形胶质细胞和乙醇相关行为中神经免疫途径的调节的贡献是 未知。该研究建议将检验总体假设，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性激活，替代剪接和与乙醇相关的很重要 行为。结合体外和体内方法，该建议将使用先进的基因组 确定LNCRNA在介导星形胶质细胞激活和乙醇中的因果关系的方法 相关行为。总体而言，我们的研究将建立用于调节基因的新分子机制 响应过度酒精暴露的表达，并有助于更好地理解 aud的发病机理。