Cognitive targets for medications development in early abstinent alcoholics

 描述(由申请人提供)：这是海伦·福克斯博士的K02独立科学家奖的申请书，她目前是耶鲁大学医学院精神病学的助理教授。2010年，Fox博士获得了NIH-NIDA资助的导师研究科学家发展奖，这使她在认知药物治疗和药物开发方面接受了无与伦比的培训。它还有助于帮助福克斯博士获得后续资金，并建立坚实的研究轨迹。福克斯博士获得了独立的资金，用于研究有和没有抑郁症状的早期戒酒患者的免疫系统变化，这些变化支撑着压力诱导的酒精渴求和认知控制(R01：AA 20095)。她也是有焦虑症状和无焦虑症状的酗酒者进行的为期12周的哌唑嗪临床试验的联合试验(R01：AA 20504)。其他项目包括评估有或没有抑郁症状的依赖个人(R03：AA022500)和危险的非依赖饮酒者(Peter F MacManus慈善信托基金)的压力和免疫系统变化潜在的谨慎和融合机制。在这项研究计划的基础上，她的职业发展目标是：1)表征有或没有焦虑和抑郁共病的酗酒者的压力和免疫系统适应，以便为药物开发提供新的治疗目标；2)随后开发更好地针对共病人群中的这些系统的定制药物。通过K02奖所提供的集中研究时间实现这些目标，对于福克斯博士保持目前的生产力水平并过渡到一名完全独立的科学家至关重要。五年的职业生涯 还提出了发展计划，包括4个培训模块：1.教学部分：校内和校外课程和讲习班；2.实用部分：监督研究项目和资助安全；3.接待4.座谈会和会议。拟议的K02研究是在申请者资助的项目框架内进行的补充项目(R01：AA 020504/R01：AA 020095)。目的是评估3周的哌唑嗪(16 mg，tid)与安慰剂在改善认知控制(Stroop，Go/No Go，Stop Signal Performance)方面的有效性，遵循个性化的意象应激源，在有和没有焦虑的酗酒者中，以及b)检查认知控制措施在同一人群中作为结果标志的有效性。拟议的探索性目标还将检查有和没有抑郁症状的酗酒者在个性化应激源后认知控制过程中潜在的细胞因子变化。父母研究和拟议的补充神经认知研究的目标都与福克斯博士的职业目标和培训计划相一致。研究抑制性控制在预测结果中的效用，以及哌唑嗪与安慰剂在加强这些机制方面的有效性，这两个目标都是一致的。此外，阐明支持这些机制的免疫系统变化也补充了为治疗开发开发新靶点的必要性。

 DESCRIPTION (provided by applicant): This is an application for a K02 Independent Scientist Award for Dr Helen Fox, who is currently an Assistant Professor in Psychiatry at Yale University School of Medicine. In 2010, Dr Fox received a NIH-NIDA funded Mentored Research Scientist Development Award which allowed her to received unparalleled training in cognitive pharmacotherapy and medications development. It was also instrumental in helping Dr Fox secure subsequent funding and establish a solid research trajectory. Dr Fox has received independent funding to examine immune system changes underpinning stress-induced alcohol craving and cognitive control in early abstinent alcoholics with and without depressive symptomatology (R01: AA 20095). She is also Co-PI of a 12 week clinical Prazosin trial in alcoholics with and without anxiety symptomatology (R01: AA 20504). Other projects include assessing discreet and converging mechanisms underlying stress and immune system changes in dependent individuals with and without depressive symptomatology (R03:AA022500) and hazardous non- dependent drinkers (Peter F MacManus Charitable Trust). On the basis of this research program, her career development goals are: 1) To characterize stress and immune system adaptations in alcoholics with and without anxiety and depressive comorbidity in order to provide novel treatment targets for medications development; 2) to subsequently develop better-tailored medications that target these systems in co-morbid populations. Attaining these goals via the focused research time afforded by the K02 award will be critical for Dr Fox to maintain her current level of productivity and transition to a fully independent scientist. A 5- year Career Development Plan is also proposed, comprising 4 training modules: 1. Didactic components: intramural and extramural courses and workshops; 2. Practical components: overseeing research projects and funding securement 3.Preceptorships 4. Symposia & Meetings. The proposed K02 research represents a supplementary project conducted within the framework of the applicants funded projects (R01: AA 020504 / R01: AA 020095). Objectives are to a) assess the efficacy of 3-weeks prazosin (16mgs t.i.d) versus placebo in improving cognitive control (Stroop, Go/No Go, Stop Signal performance), following a personalized imagery stressor in alcoholics with and without anxiety, and b) examine the utility of cognitive control measures as markers of outcome in the same population. The proposed exploratory aims will additionally examine cytokine changes underlying cognitive control processes following a personalized stressor in alcoholics with and without depressive symptomatology. The objectives of both parent studies and the proposed supplementary neurocognitive research are compatible with Dr Fox's career goals and training plan. Examining the utility of inhibitory control in predicting outcome and the efficacy of prazosin versus placebo in strengthening these mechanisms is compatible with both goals. In addition, elucidating immune system changes underpinning these mechanisms also complements the need to development novel targets for treatment development.