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

项目摘要 酒精使用障碍(AUD)每年导致全球250多万人死亡，其中58人以上 全球损失了100万个生命年，仅在美国就损失了2200亿美元的经济成本。此外，澳元 与其他各种疾病(如创伤性脑损伤、创伤后应激障碍、 焦虑、抑郁)本身的患病率正在上升，这在一定程度上要归功于临床人数的增加 意识。在过去的20年里，一种神经系统显示出了巨大的潜力 促肾上腺皮质激素释放因子(CRF)是AUD及其伴发疾病的治疗靶点，尤其是CRF 通过CRF-1受体(CRFR1)传递信号。神经科学的最新进展允许创造出 复杂的遗传动物模型，使实验人员能够针对特定的神经元群体和 根据传入神经、投射目标和/或，检查它们在网络动力学和行为中的角色 分子签名。在这里，我们建议通过建立和验证CRFR1：CRE大鼠来创建一个这样的模型 用于AUD的神经生物学和相关精神疾病的临床前研究。 这个项目属于NIAAA任务的范围，目的是支持神经科学中与酒精相关的研究。 该项目还通过支持新模式的研究，满足了R21筹资机制的标准 有可能对生物医学研究产生重大影响的系统。这项工作的长期目标 本申请中提出的是创建一种遗传动物模型，该模型可以由 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信号已被认为是一个有前途的治疗靶点。拟议的AIMS将使用 BAC重组工程与密歇根大学转基因公司合作创建CRFR1：Cre大鼠 核心，将支持CRFR1：CRE大鼠繁殖群体的创建，并将支持开展以下工作 这一新的遗传动物模型的解剖学、电生理学和行为学验证。

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.