YALE-SCORE ON SEX DIFFERENCES IN ALCOHOL USE DISORDER

我们建议的耶鲁专业卓越研究中心(SCORE)关于酒精使用中的性别差异 紊乱(AUD)汇集了一支由领先的基础和临床科学专家组成的团队，致力于 跨学科、翻译、跨物种的研究计划，旨在确定新的治疗方法 解决最近女性澳门氏症发病率激增的问题。在过去的10年里，女性的澳门氏症患病率 增加了84%，相当于全美1050万女性。酒精的使用排在第三位。 在美国，可预防的发病率和死亡率的原因和女性饮酒者的经历加剧 与男性相比，与饮酒相关的健康风险。FDA批准的治疗AUD的药物 疗效相对较低，都是在男性样本中开发的，没有不同的目标因素 保持女性饮酒。大量数据表明，女性更有可能饮酒以 调节消极情绪和压力，而男性更有可能因酒精相关的积极因素而饮酒 增援。Koob&Volkow194开发了一个成瘾周期的启发式框架，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“上瘾的阴暗面”。这一阶段的神经适应确定了奖赏缺陷和压力 过度饮酒，这会导致强迫性饮酒。使用这个负强化模型来指导我们的研究，我们 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 新陈代谢和性类固醇激素，它们被假设为不同地刺激酒精消费 在女人身上。到目前为止，还没有一致的努力将性别作为一个生物变量(SABV) 进入澳大利亚的药物开发。因此，我们耶鲁分数的重点代表了一个很高的研究 NIAAA和ORWH的优先主题。我们提出了三个相互关联和共享的项目 目标，每个目标都提供了独特的贡献，以提供信息和加快AUD疗法的发展 对患有澳元的女性来说。这些项目将得到三个核心和一个机构环境的支持 支持翻译科学的特殊资源和基础设施。我们的具体目标和目标 耶鲁大学的分数是：目标1：使用神经生物学知识的方法，专注于 提供信息并加快针对压力和性行为的适宜疗法的开发 负面情绪，这是女性饮酒的主要原因。目标2：导师评分-早期调查人员 成为关注酒精和女性健康的下一代生物医学和行为研究人员 横跨T1到T4的翻译光谱。目标3：成为机构、区域和国家资源 通过提供从T1到T4的翻译，促进与酒精使用有关的性别差异的研究 专家咨询，支持教师培训奖，利用性和酒精使用的国家级数据 为治疗和政策提供信息，并提供外展和传播方案。

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.