YALE-SCORE ON SEX DIFFERENCES IN ALCOHOL USE DISORDER

耶鲁大学酒精使用障碍性别差异评分

• 批准号: 10599817
• 负责人: SHERRY ANN MCKEE
• 金额: $ 167.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-10 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599817
• 关键词: Accounting; Address; Affect; Alcohol consumption; Alcohols; Area; Award; Basic Science; Behavioral; Biological; Biology; Biomedical Research; Brain; Cardiovascular Diseases; Centers of Research Excellence; Clinical Sciences; Cognitive deficits; Collaborations; Communities; Consultations; Darkness; Data; Development; Ensure; Environment; Ethanol Metabolism; FDA approved; Faculty; Funding; Goals; Gonadal Steroid Hormones; Health; Healthcare; Infrastructure; Institution; Laboratories; Leadership; Malignant Neoplasms; Mentors; Modeling; Morbidity - disease rate; National Institute on Alcohol Abuse and Alcoholism; Negative Reinforcements; Neurobiology; Neuroimmune; Neurosciences; Pharmaceutical Preparations; Policies; Positive Reinforcements; Positron-Emission Tomography; Psychiatry; Public Health; Publications; Research; Research Personnel; Research Priority; Resources; Rewards; Risk; Role; Sampling; Sex Differences; Side; Specialized Center; Stress; Structure; Substance abuse problem; System; Teacher Professional Development; Therapeutic; Translating; Translational Research; Translations; United States; Withdrawal; Woman; Women' s Health; addiction; alcohol abuse therapy; alcohol use disorder; behavioral pharmacology; cerebral atrophy; drinking; economic cost; experience; faculty support; heuristics; hypothalamic-pituitary-adrenal axis; improved; interest; liver inflammation; men; metabolomics; mortality; negative affect; neuroadaptation; neurochemistry; neurotoxicity; next generation; novel therapeutics; outreach; outreach program; programs; recruit; response; sex; success; therapeutic target; translational approach; translational pipeline; translational scientist

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.

我们提议建立耶鲁大学关于酒精使用性别差异的专业研究卓越中心 (SCORE) 疾病（AUD）汇集了领先的基础和临床科学专家团队，以追求 跨学科、转化、跨物种的研究计划，旨在确定治疗性小说 解决最近女性澳元比率激增的问题。 在过去 10 年中，女性澳元比率已经上升。 增加了 84%，即全美有 1050 万名女性饮酒，位居第三。 美国可预防的发病率和死亡率的原因以及女性饮酒者的情况加剧 与 FDA 批准的 AUD 药物相比，饮酒带来的健康风险。 功效相对较低，全部都是以男性样本开发的，并且没有针对差异化因素 大量数据表明，女性更有可能饮酒。 调节负面情绪和压力，而男性更有可能因酒精相关的积极因素而饮酒 Koob 和 Volkow194 开发了一个成瘾循环的启发式框架，其中 “戒断/负面情绪阶段”还包括因压力和其他负面情绪状态而饮酒 被称为“成瘾的阴暗面”的神经适应在这个阶段识别奖励缺陷和压力。 我们利用这种负强化模型来指导我们的研究。 计划针对关键大脑结构、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，这些激素竞相不同地刺激饮酒 迄今为止，还没有一致的努力将性别作为一个生物学变量（SABV）。 在 AUD 药物开发方面，我们的耶鲁 SCORE 代表了一项高度研究的重点。 我们提出了三个相互关联和共享的项目。 目标，每个目标都为促进和加速 AUD 疗法的开发做出独特的贡献 该项目将由三个核心和一个具有 AUD 的机构环境支持。 支持转化科学的特殊资源和基础设施。 耶鲁大学 SCORE 旨在： 目标 1：使用神经生物学方法，重点关注“黑暗面” 成瘾”，以告知并加速针对压力和性别的适当疗法的开发 目标 2：指导 SCORE-早期调查人员 成为专注于酒精和女性健康的下一代生物医学和行为研究人员 跨越 T1 到 T4 翻译范围 目标 3：成为机构、区域和国家资源。 通过提供 T1 到 T4 翻译，激发与饮酒相关的性别差异的研究 专家咨询、支持教师培训奖励、利用有关性和酒精使用的国家数据 为治疗和政策提供信息，并提供外展和传播计划。