Generation and validation of a CRFR1-cre transgenic rat to study alcohol dependence

用于研究酒精依赖的 CRFR1-cre 转基因大鼠的生成和验证

• 批准号: 9761939
• 负责人: NICHOLAS WARREN GILPIN
• 金额: $ 17.84万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-10 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761939
• 关键词: Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Anatomy; Animal Genetics; Animal Model; Animals; Anxiety; Awareness; Bacterial Artificial Chromosomes; Behavior; Behavioral; Biological Models; Biomedical Research; Brain; Brain region; Breeding; CRF receptor type 1; Cells; Cessation of life; Clinical; Complement; Complex; Core Facility; Corticotropin-Releasing Hormone; DNA; Disease; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Financial cost; Funding Mechanisms; Generations; Goals; Immunohistochemistry; In Situ Hybridization; Intake; Investigation; Justice; Label; Literature; Mediating; Mental Depression; Mental disorders; Michigan; Mission; Modeling; Molecular Profiling; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Neurons; Neurosciences; Oocytes; Pattern; Pharmaceutical Preparations; Population; Post-Traumatic Stress Disorders; Prevalence; Property; Proteins; Rattus; Receptor Signaling; Recording of previous events; Reinforcement Schedule; Relapse; Research; Research Personnel; Role; Self Administration; Signal Transduction; Site; System; Technical Expertise; Techniques; Testing; Tomatoes; Transgenes; Transgenic Model; Transgenic Organisms; Traumatic Brain Injury; United States; Universities; Validation; Work; addiction; alcohol effect; alcohol research; alcohol use disorder; base; behavior measurement; cost; drug withdrawal; experience; falls; negative affect; nerve supply; optogenetics; postsynaptic neurons; pre-clinical; preclinical study; receptor; relating to nervous system; therapeutic target; years of life lost

Project Summary Alcohol Use Disorder (AUD) is responsible each year for more than 2.5 million deaths worldwide, more than 58 million life years lost worldwide, and $220 billion in financial cost in the United States alone. Furthermore, AUD is highly co-morbid with various other conditions (e.g., traumatic brain injury, post-traumatic stress disorder, anxiety, depression) that are themselves increasing in prevalence, thanks in part to increased clinical awareness. Over the last 20 years, one neural system that has shown significant promise as a potential therapeutic target for AUD and co-morbid disorders is corticotropin-releasing factor (CRF), and especially CRF signaling through the CRF-1 receptor (CRFR1). Recent advances in neuroscience allow for the creation of sophisticated genetic animal models that allow experimenters to target specific neuronal populations and examine their role in network dynamics and behavior, based on afferent innervation, projection target, and/or molecular signature. Here we propose to create one such model by developing and validating a CRFR1:Cre rat for use in pre-clinical studies on the neurobiology of AUD and related psychiatric conditions. This project falls within the scope of the NIAAA mission to support alcohol-related research in neuroscience. This project also meets the criteria for the R21 funding mechanism by supporting investigation of new model systems with the potential for significant impact on biomedical research. The long-term goal of the work proposed in this application is to create a genetic animal model that can be distribited and used by multiple investigators in various pre-clinical neuroscience fields (including but not limited to pre-clinical AUD research) where CRFR1 signaling has been implicated as a promising therapeutic target. The proposed aims will use BAC recombineering to create a CRFR1:Cre rat in partnership with the University of Michigan Transgenics Core, will support creation of a breeding colony of CRFR1:Cre rats, and will support work that performs anatomical, electrophysiological, and behavioral validation of this new genetic animal model.

项目摘要 饮酒障碍（AUD）每年负责全球250万人死亡，超过58人 全世界丧生的一百万年代，仅在美国，就损失了2200亿美元的财务成本。此外，Aud 与其他各种情况（例如，创伤性脑损伤，创伤后应激障碍， 焦虑，抑郁症本身在患病率上增加，部分原因是临床增加 意识。在过去的20年中，一个神经系统表现出巨大的希望作为潜力 AUD和合并症疾病的治疗靶点是促脑性释放因子（CRF），尤其是CRF 通过CRF-1受体（CRFR1）信号传导。神经科学的最新进展允许创建 复杂的遗传动物模型，使实验者能够针对特定的神经元种群和 基于传入的神经支配，投影目标和/或 分子签名。在这里，我们建议通过开发和验证CRFR1：CRE RAT创建一个这样的模型 用于临床前研究AUD和相关精神疾病的神经生物学。 该项目属于NIAAA任务的范围，以支持与酒精相关的神经科学研究。 该项目还通过支持对新模型的调查来符合R21资金机制的标准 对生物医学研究产生重大影响的系统。工作的长期目标 在本应用中提出的是创建一个遗传动物模型，该模型可以由多个分发和使用 各种临床前神经科学领域的研究人员（包括但不限于临床前AUD研究） CRFR1信号传导已被视为有前途的治疗靶标。拟议的目标将使用 与密歇根大学转基因公司合作创建CRFR1：CRE RAT的BAC重组 核心，将支持创建CRFR1：CRE大鼠的繁殖殖民地，并将支持执行的工作 这种新的遗传动物模型的解剖学，电生理和行为验证。