lncRNA Gas5 dysregulation alters ethanol drinking behavior and ethanol-related phenotypes

lncRNA Gas5失调改变乙醇饮用行为和乙醇相关表型

基本信息

批准号：
10464571
负责人：
Sonja Lorean Plasil
金额：
$ 4.68万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-03 至 2023-03-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10464571
关键词：
Abnormal coordination Acute Addictive Behavior Adult Alcohol Phenotype Alcohol consumption Alcohol dependence Alcoholism Alcohols American Amygdaloid structure Animals Attention Behavior Bilateral Brain Brain Diseases Brain region CRISPR/Cas technology Cause of Death Chronic Clinical Cocaine Complex Consumption Dependovirus Development Disease Disease Progression Drug Addiction Ethanol Financial compensation Foundations Gene Expression Genetic Transcription Genome Glucocorticoid Receptor Glucocorticoids Goals Growth Guide RNA Human Immune Immune signaling In Situ Hybridization Individual Intake Knock-out Laboratories Learning Link Manuscripts Medial Mediating Mental disorders MicroRNAs Molecular Molecular Mechanisms of Action Motivation Motor Mus Mutagenesis Mutate Mutation Neurobiology Neuroimmune Neurons Neurosciences Nucleus Accumbens Operative Surgical Procedures Outcome Pathogenesis Pathway interactions Patients Persons Phenotype Porifera Prefrontal Cortex Process Psychiatric Diagnosis RNA Regulation Relapse Research Research Personnel Rewards Role Sequence Homology Substance abuse problem System Technical Expertise Techniques Testing Training United States Untranslated RNA Withdrawal Work Writing addiction alcohol behavior alcohol exposure alcohol misuse alcohol relapse alcohol response alcohol testing alcohol use disorder anxiety-like behavior biological adaptation to stress collaborative environment craving design drinking drinking behavior emotional distress executive function experimental study human disease in vivo insight interest neuroinflammation neuronal growth new therapeutic target overexpression pre-clinical preference promoter response targeted treatment training opportunity transcription factor transcriptome transcriptome sequencing transcriptomics vapor

项目摘要

Project Summary Alcohol use disorder (AUD) is a chronic, debilitating, and relapsing brain disease. An overwhelming number of people die yearly due to alcohol-related causes; however, the mechanism(s) of action are challenging to decipher and remain largely elusive. Long noncoding RNAs (lncRNAs) are key regulators of the genome; persistent transcriptional changes induced by chronic ethanol exposure is a hypothesized mechanism for AUD development, withdrawal, and relapse. Our laboratory and others have shown that ethanol-responsive lncRNAs have the ability to directly regulate ethanol- related behavior when mutated in vivo, but only a handful have been characterized to date. In this proposal, I will learn and apply state-of-the-art CRISPR/Cas9 techniques to functionally investigate ethanol-responsive lncRNA Gas5 for its regulation of ethanol drinking and ethanol-related behaviors. As ethanol alters gene expression and molecular pathways that regulate neuroinflammation, I want to target an ethanol-responsive and highly-interconnected competing endogenous RNA (ceRNA) lncRNA that may coordinate large endogenous immune networks related to AUD. I will focus on in vivo CRISPR/Cas9 modulation of a specific ‘hub’ lncRNA of interest, growth arrest-specific 5 (Gas5). Gas5 acts as a ceRNA to regulate immune signaling, is significantly and persistently downregulated following chronic intermittent ethanol vapor exposure and has been shown to reduce cocaine-intake, linking Gas5 to substance abuse. It is therefore of substantial interest to test the hypothesis that Gas5 is a key determinant of ethanol action. Gas5 will be knocked out in a temporal, cellular, and brain region-specific manner to investigate its role on ethanol drinking. Upon completion of this project, I will have advanced our understanding for the molecular impact of ethanol- responsive lncRNA Gas5 and how it relates to addictive behavior. This project will provide substantial training opportunities, a strong research foundation applicable to a variety of scientific fields, and a collaborative environment with other researchers in the field including the Integrative Neuroscience Initiative on Alcoholism – Neuroimmune consortium. A wealth of technical skills ranging from bench work to complex surgical techniques, the understanding and development of project design, and several scientific writing manuscript prospects are available within each aim that will be valuable for my continued scientific training.

项目摘要酒精使用障碍（AUD）是一种慢性，令人衰弱的脑部疾病。压倒性的数量人们每年由于与酒精有关的原因而死亡；但是，动作的机制挑战了破译并在很大程度上难以捉摸。长的非编码RNA（LNCRNA）是基因组的关键调节剂。持续的转录变化引起通过慢性乙醇暴露是一种假设的AUD开发，退出和缓解的机制。我们的实验室和其他人表明，乙醇反应性的lncRNA具有直接调节乙醇的能力当体内突变时相关行为，但迄今为止只有少数被表征。在这个建议中，我将学习并应用最先进的CRISPR/CAS9技术来调查乙醇响应 LNCRNA GAS5调节乙醇饮用和与乙醇相关的行为。随着乙醇改变调节神经炎症的基因表达和分子途径，我想靶向乙醇反应性和高度交互连接的竞争性内源RNA（Cerna）lncRNA可能协调与AUD相关的大型内源性免疫网络。我将重点介绍特定的“枢纽” lncrna的体内CRISPR/CAS9调制，越来越多的逮捕特定5 （GAS5）。 GAS5充当调节免疫信号传导的CERNA，显着且持续下调慢性间歇性乙醇蒸气暴露后，已被证明可减少可卡因 - 智力 GAS5滥用药物。因此，测试煤气5是关键的假设是很大的兴趣乙醇作用的决定因素。 GAS5将以临时，细胞和大脑特异性方式淘汰调查其在乙醇饮用中的作用。该项目完成后，我将提高我们对乙醇的分子影响的理解响应型lncrna gas5及其与其他行为的关系。该项目将提供大量培训机会，强大的研究基金会适用于各种科学领域，以及协作与该领域的其他研究人员的环境，包括关于酒精中毒的综合神经科学倡议 - 神经免疫财团。从板凳工作到复杂的手术技术等丰富的技术技能，项目设计的理解和发展以及几个科学写作手稿的前景是在每个目标中都可以使用，这对于我的持续科学培训很有价值。