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

项目摘要 酒精使用障碍（AUD）每年在全球造成250多万人死亡，其中58 全世界损失了100万生命年，仅在美国就损失了2200亿美元的经济成本。此外，AUD 与各种其它病症高度共病（例如，创伤性脑损伤，创伤后应激障碍， 焦虑，抑郁），这些疾病本身的患病率也在增加，部分原因是临床 意识在过去的20年里，一个神经系统已经显示出巨大的潜力， AUD和共病疾病的治疗靶点是促肾上腺皮质激素释放因子（CRF），尤其是CRF 通过CRF-1受体（CRFR 1）进行信号传导。神经科学的最新进展允许创建 复杂的遗传动物模型，允许实验人员针对特定的神经元群体， 根据传入神经支配、投射目标和/或 分子特征在这里，我们建议通过开发和验证CRFR 1：Cre大鼠来创建一个这样的模型。 用于AUD神经生物学和相关精神疾病的临床前研究。 该项目福尔斯NIAAA的使命范围，以支持神经科学中与酒精相关的研究。 该项目通过支持新模型的研究，也符合R21资助机制的标准。 对生物医学研究具有重大影响潜力的系统。工作的长期目标 本申请中提出的是创建一种遗传动物模型，其可以由多个基因组分配和使用。 各种临床前神经科学领域的研究者（包括但不限于临床前AUD研究） 其中CRFR 1信号传导被认为是有希望的治疗靶点。拟议的目标将使用 BAC重组工程与密歇根大学转基因公司合作创建CRFR 1：Cre大鼠 核心，将支持创建一个CRFR 1：Cre大鼠繁殖群，并将支持执行以下工作： 解剖学、电生理学和行为学验证了这种新的遗传动物模型。

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.