YALE-SCORE ON SEX DIFFERENCES IN ALCOHOL USE DISORDER

我们提议的耶鲁大学卓越研究中心（SCORE）关于酒精使用的性别差异 疾病（AUD）汇集了一个领先的基础和临床科学专家团队， 跨学科，翻译，跨物种的研究计划，旨在确定新的治疗方法， 解决最近女性澳元汇率飙升的问题。在过去的10年里，妇女的澳元比率 增加了84%，在美国有1050万女性。酒精使用是第三大 在美国，可预防的发病率和死亡率的原因， 与男性相比，饮酒对健康的危害更大。FDA批准的AUD药物 相对较低的功效，所有这些都是用男性样本开发的，没有一个目标因素， 保持女性饮酒。大量数据表明，女性更有可能喝酒， 调节负面情绪和压力，而男性更容易因酒精相关的积极因素而饮酒 加固. Koob和Volkow 194已经开发了成瘾循环的启发式框架，其中 “戒断/负面情绪阶段”包括因压力和其他负面情绪状态而饮酒， 被称为“上瘾的黑暗面”。在这个阶段的神经适应识别奖励赤字和压力 饮酒过量，导致强迫性饮酒。我们使用这个负强化模型来指导我们的研究， 计划针对关键的大脑结构，神经化学系统，HPA轴活动，神经免疫功能，酒精 代谢，和性类固醇激素，这是假设差异激励酒精消费 在女人身上。到目前为止，还没有一个协调一致的努力，将性别作为一个生物变量（SABV） 开发AUD药物。因此，我们的耶鲁评分的重点代表了高研究 NIAAA和ORWH的优先主题。我们提出了三个项目，将有相互关联和共享 目标，每个目标都提供了独特的贡献，以告知和加快AUD治疗的发展 对于AUD的女性来说。这些项目将得到三个核心和一个体制环境的支持， 卓越的资源和基础设施，以支持转化科学。我们的具体目标和目的 耶鲁评分是：目标1：使用神经生物学的方法，专注于“黑暗的一面， 成瘾“，以告知和加速针对压力的适合性别的治疗方法的发展， 负面影响，这差异保持妇女饮酒。目的2：导师评分-早期研究者 成为下一代专注于酒精和女性健康的生物医学和行为研究人员 跨越T1到T4平移谱。目标3：成为机构、区域和国家资源 通过提供T1到T4翻译，激发对与酒精使用相关的性别差异的研究 专家咨询，支持教师培训奖，利用国家性和酒精使用数据， 为治疗和政策提供信息，并提供一个推广和传播方案。

Our proposed Yale-Specialized Center of Research Excellence (SCORE) on sex differences in alcohol use disorder (AUD) brings together a team of leading basic and clinical science experts to pursue an interdisciplinary, translational, cross-species program of research aimed at identifying novel therapeutics to address the recent surge in rates of AUD in women. Over the past 10 years, rates of AUD in women have increased by 84%, translating to 10.5 million women across the United States. Alcohol use is the third leading cause of preventable morbidity and mortality in the United States and women drinkers experience exacerbated health risks associated with alcohol consumption when compared to men. FDA-approved medications for AUD have relatively low efficacy, all were developed with samples of men, and none target factors that differentially maintain drinking in women. A considerable body of data identifies that women are more likely to drink to regulate negative affect and stress, while men are more likely to drink for alcohol-related positive reinforcement. Koob & Volkow194 have developed a heuristic framework of the addiction cycle, where the ‘withdrawal/negative affect stage’ involves drinking motivated by stress and other negative affect states, also termed ‘the dark side of addiction’. Neuroadaptations during this stage identify reward deficits and stress surfeits, which drive compulsive drinking. Using this negative reinforcement model to guide our research, we plan to target key brain structures, neurochemical systems, HPA-axis activity, neuroimmune function, alcohol metabolism, and sex steroid hormones, which are hypothesized to differentially motivate alcohol consumption in women. To date, there has not been a concerted effort to incorporate sex as a biological variable (SABV) into AUD medication development. Consequently, the focus of our Yale-SCORE represents a high research priority topic for both NIAAA and ORWH. We propose three Projects that will have inter-related and shared goals, with each providing unique contributions to inform and expedite the development of AUD therapeutics for women with AUD. The Projects will be supported by three Cores and an institutional environment with exceptional resources and infrastructure to support translational science. Our specific aims and objectives of the Yale-SCORE are to: AIM 1: Use a neurobiologically-informed approach focusing on the ‘dark side of addiction’ to inform and expedite the development of sex-appropriate therapeutics targeting stress and negative affect, which differentially maintain drinking in women. AIM 2: Mentor SCORE-Early Investigators to become the next generation of biomedical and behavioral researchers focused on alcohol and women’s health spanning the T1 to T4 translational spectrum. AIM 3: Be an institutional, regional, and national resource galvanizing the study of sex differences in relation to alcohol use across T1 to T4 translation by providing expert consultation, supporting faculty training awards, leveraging national data on sex and alcohol use to inform treatment and policy, and providing a program of outreach and dissemination.