CNS Effects of Alcohol: Cellular Neurobiology

项目摘要 本申请是对AA006420的管理核心Scripps的行政补充 研究院的酒精研究中心(TSRI-ARC)，直接成本55,238美元。这样做的目的是 补充请求是为了支持数据管理、分析、解释和发布来自 首次完成了对患有酒精使用障碍(AUD)的人类的下丘脑素(食欲素)拮抗剂研究。注册以下项目 这项2a期研究是在TSRI-ARC的第39年完成的，以满足临床研究的特定目标 组件。这项研究的住院部分与Covid相关的夜间人员短缺 合作机构需要将学科招生延长至2022年11月，以优化学习 样本量截止日期为12/31/22。延长的注册期限仅允许粗略 数据录入、管理和顶线结果分析，以完成赠款的最终进度报告 在Clinicaltrials.gov上发布topline结果。对结果的全面分析对于确定 临床前降克素拮抗剂研究的方向，包括在40年测量什么参数 TSRI-ARC神经药理学研究部分，主要侧重于研究 AUD动物模型中的下丘脑肌素。临床分析的资金不包括在续签中。 应用程序，因为无法预测上述情况需要延长 由于注册期较长，因此无法在拟议的时限内完成数据分析。此外， 我们选择在续签中日落临床部分，以及前几年的任何结转资金 支出后，中心预算削减了10%，间接成本率自 已提交续订。因此，不可能在更新时重新预算资金以支持Suvorexant 在不对更新的具体目标产生重大负面影响的情况下进行人体实验室数据分析 项目。然而，梅森博士在续签的第40年担任行政核心主任的部分职责是 促进基础研究的翻译，包括人体研究的反向翻译，以及这些临床研究 数据对这一目标至关重要。我们明白，在第一阶段要求行政补充是不寻常的。 资金周期的一年，但在神经药理学部分等待一年会适得其反 实施一项研究计划，可能需要根据在下丘脑中收集的信息进行修改 拮抗剂的临床概念验证研究。这个项目很有可能发挥出持续的、强有力的 将基础科学成果转化为以神经科学为基础的新疗法对该领域的影响 澳元发展战略。重要的是，业界有兴趣将这一目标向前推进，作为治疗澳元的一种方法。如果 所要求的资金将被授予，这样的翻译目标可以实现，计划的信息将被 可用于指导神经药理学部分和酒精研究社区。

Project Summary This request is for an administrative supplement to the Administrative Core of AA006420, The Scripps Research Institute’s Alcohol Research Center (TSRI-ARC), for $55,238 in direct costs. The purpose of this supplement request is to support data management, analysis, interpretation, and publication of results from the first completed hypocretin (orexin) antagonist study in humans with alcohol use disorder (AUD). Enrollment for this Phase 2a study was completed in Year 39 of the TSRI-ARC to meet a Specific Aim of the Clinical Component. Covid-related overnight staffing shortages for the inpatient component of the study at a collaborating institution necessitated extending subject enrollment through November 2022 to optimize study sample size by the end date of the grant on 12/31/22. The extended enrollment period only permitted cursory data entry, management, and analysis of top-line results to complete the final progress report for the grant and the posting of topline results on clinicaltrials.gov. Comprehensive analysis of results is critical for determining the direction of the pre-clinical hypocretin antagonist studies, including what parameters to measure in Year 40 of the TSRI-ARC Neuropharmacology Research Component, which has a primary focus on studying hypocretin in animal models of AUD. Funding for the clinical analyses was not included in the renewal application because there was no way to anticipate that the above circumstances would necessitate extending the enrollment period and preclude completion of data analysis within the proposed timeframe. Furthermore, we elected to sunset the Clinical Component in the renewal and any carryover funds from previous years have been expended, the Center budget was cut by 10%, and our indirect cost rate increased by 4% since the renewal was submitted. Thus, it is not possible to re-budget funds in the renewal to support the suvorexant human laboratory data analyses without significantly negatively impacting the Specific Aims of the renewal projects. However, part of Dr. Mason’s role as Director of the Administrative Core in Year 40 of the renewal is to facilitate the translation of basic research, including back translation from human studies, and these clinical data are critical to this aim. We understand it is unusual to request an administrative supplement in the first year of a funding cycle, but it is counterproductive to wait a year while the Neuropharmacology Component implements a research plan that may require modification based on information collected in the hypocretin antagonist clinical proof-of-concept study. This project has a high likelihood of exerting a sustained, powerful influence on the field by translating basic science findings into a novel neuroscience-based therapeutic strategy for AUD. Importantly, there is industry interest in moving this target forward as a treatment for AUD. If the requested funds are awarded, such translational goals can be met, and planned information will be available to guide the Neuropharmacology Component and the alcohol research community.