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.

我们提议的耶鲁大学专业研究中心卓越研究中心（得分）关于酒精使用性别差异 疾病（AUD）汇集了一支领先的基础和临床科学专家团队 跨学科，翻译，跨物种研究计划，旨在识别新的疗法 解决了近期女性AUD率的激增。在过去的10年中，女性的AUD率有 在美国，增加了84％，转化为1,050万妇女。饮酒是第三大领先 美国和女性饮酒者经历的可预防发病率和死亡率的原因加剧了 与男性相比，与饮酒有关的健康风险。 FDA批准的AUD药物 效率相对较低，所有效率都是由男性样本开发的，没有差异性因素 维持女性饮酒。大量数据表明，女性更有可能喝酒 调节负面影响和压力，而男性则更有可能以酒精相关的阳性喝酒 加强。 Koob＆volkow194已经开发了成瘾周期的启发式框架 “戒断/负面影响阶段”涉及由压力和其他负面影响状态激励的饮酒，也涉及 被称为“成瘾的黑暗面”。在此阶段，神经适应识别奖励定义和压力 SURFEITS，可以驱动强迫性饮酒。使用这种负面加强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 代谢和性立体激素，假设有不同的促进饮酒的动力 在女性中。迄今 进入AUD用药开发。因此，我们耶鲁分数的重点代表了一项较高的研究 NIAAA和ORWH的优先主题。我们提出了三个将相互关联和共享的项目 目标，每个人都提供独特的贡献，以告知和加快AUD疗法的发展 适用于有声的女性。这些项目将得到三个核心和一个机构环境的支持 支持转化科学的卓越资源和基础设施。我们的具体目的和目标 耶鲁大学的得分是：目标1：使用针对“黑暗的一面”的神经生物学知情方法 成瘾'以告知和加快针对性压力的性治疗的发展 负面影响，妇女维持饮酒的程度不同。目的2：指导得分与研究人员到 成为下一代生物医学和行为研究人员，专注于酒精和妇女健康 跨越T1到T4翻译频谱。目标3：成为机构，地区和国家资源 通过提供的性别差异的研究来镀以通过提供的性别差异的研究 专家咨询，支持教师培训奖，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，并提供宣传和传播计划。