LNCRNA REGULATION OF GENE EXPRESSION & BEHAVIOR

项目总结 酒精使用障碍(AUD)是现代世界的一个主要社会经济问题。急、慢性酒精 已知暴露会导致系统范围内多个大脑区域和 细胞类型。哺乳动物基因组包括蛋白质编码转录本和非蛋白质编码转录本， 其中不到2%是蛋白质编码的。尽管蛋白质编码基因的数量超过了蛋白质编码基因，但它的生物学功能 大多数非编码转录本在很大程度上仍然不为人知。最大的一类非编码转录本是长的 非编码RNA(LncRNAs)，在操作上被定义为超过200个核苷酸的转录本 不为蛋白质编码的长度。到目前为止，对lncRNA进行的大多数研究都表明了它的关键作用。 在基因表达调控中的作用。此外，lncRNA对于选择性剪接也很重要。 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过程 蛋白质。选择性剪接对于建立免疫系统的上下文相关反应至关重要。 此前已有研究表明，长期酒精暴露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胶质细胞类型，数量超过神经元和其他胶质细胞。 在中枢神经系统(CNS)。星形胶质细胞连续地铺满整个中枢神经系统，在 多种生物学功能，包括对中枢神经系统损伤的反应，激活神经免疫通路，以及 调节行为。星形胶质细胞已知与酒精敏感和消耗有关；然而， LncRNAs对星形胶质细胞神经免疫通路和酒精相关行为的调节作用 未知。这项研究提案将检验lncRNAs在星形胶质细胞中表达的总体假设 对于协调酒精诱导的神经免疫激活、选择性剪接和酒精相关 行为。使用体外和体内相结合的方法，这项提议将使用先进的基因组 确定lncRNAs在调节星形胶质细胞激活和乙醇中的因果关系的方法 相关行为。总之，我们的研究将建立新的调控基因的分子机制。 表达对过量酒精暴露的反应，并有助于更好地了解 AUD的发病机制。

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.