Neuroimmune Treatment for AUD: Testing Moderators of Clinical Response and Mechanisms of Action

项目摘要/摘要 在过去一年患有AUD的患者中，只有一小部分人接受了治疗。因此，发展 治疗AUD的新的、有效的药物疗法是一个高度优先的研究重点，可能导致更高的治疗 利用率和成功率。建立治疗反应的调节剂和作用机制是一种 朝着确定良好临床反应的预测因素和进一步推进精确医学迈出了必要的一步。 调节免疫功能是治疗成瘾的一个很有前途的靶点。通过激活免疫 细胞受体，长期大量饮酒会导致促炎状态，从而导致AUD 症状学。消极情绪是多方面的结构，是AUD的共同特征 与较差的治疗结果有关，并可能与长期饮酒引起的炎症有关。 消炎疗法被证明可以降低精神病患者的负面影响水平。 精神错乱。因此，减少负面影响的方面可能是一种潜在的行动机制，涉及 AUD的神经免疫调节。关于候选主持人，跨学科的研究表明， 尤其明显的炎症特征可能更适合神经免疫治疗。考查 对免疫治疗反应的性别差异也得到了几个领域的研究和支持 被美国国立卫生研究院描述为可以为临床干预提供信息的优先考虑因素。这项建议是基于 最近的迹象表明，异丁司特，一种神经免疫调节剂，是一种潜在有效的药物治疗 澳元。赞助商实验室对异丁司特的初步筛查显示，在压力暴露后， 异丁司特促进正性情绪的较强恢复，增强负性情绪对心理健康的影响。 渴望。这个NRSA应用程序的目标是促进我作为一名临床科学家的发展 有关AUD的药物开发、心理神经免疫学和定量方法。这项提议将 来自一项正在进行的、由伊布司特资助的为期12周的临床试验，该试验招募了一名寻求治疗的样本 澳元。鉴于对这类疗法如何在澳大利亚和澳大利亚的人体样本中发挥作用的有限了解 世卫组织对治疗反应最敏感，拟议的研究将调查临床反应的潜在调节因素 以及通过利用异丁司特临床试验的数据来发挥作用机制。具体地说，目标1测试 假设负面情绪的各个方面将显著地调节治疗和重型之间的关系 喝酒。目的#2测试外周促炎症生物标记物和性别将作为 异丁司特临床反应的调节因子。这些目标将使用复杂的分析方法进行测试 包括纵向、多层次的缓和和调解模式。本研究代表了一项重要的 在我的指导团队的支持下，我的科学研究人员 发展成为对药物开发感兴趣的独立临床酒精研究人员。

PROJECT SUMMARY/ ABSTRACT Only a small proportion of individuals with past-year AUD received treatment. As such, development of novel, efficacious pharmacotherapies for AUD is a high research priority that may lead to higher treatment utilization and success rates. Establishing moderators of treatment response and mechanisms of action is an imperative step towards identifying predictors of good clinical response and furthering precision medicine. Modulation of immune function is one promising treatment target for addiction. Through activation of immune cell receptors, sustained heavy alcohol use induces a proinflammatory state, which contributes of AUD symptomatology. Negative affect is multi-faceted construct and common feature of AUD that is consistently associated with poorer treatment outcomes and may be linked to inflammation induced by chronic alcohol use. Anti-inflammatory therapies are shown to reduce levels of negative affect among individuals with psychiatric disorders. As such, reductions in facets of negative affect may be a potential mechanism of action involved in neuroimmune modulation in AUD. In regard to candidate moderators, research across disciplines shows that a particularly pronounced inflammatory profile might be more amenable to neuroimmune treatment. Examination of sex differences in response to immune treatment is also supported by several fields of research and delineated by NIH as a priority consideration that can inform clinical interventions. This proposal is based on recent indications that ibudilast, a neuroimmune modulator, is a potentially efficacious pharmacotherapy for AUD. An initial screening of ibudilast in the Sponsor's laboratory showed that following stress exposure, ibudilast promoted a stronger recovery of positive affect and strengthened the influence of negative affect on craving. The objective of this NRSA application is to foster my development as a clinical scientist with a focus on medications development for AUD, psychoneuroimmunology, and quantitative methods. This proposal will draw from an ongoing and funded 12-week clinical trial of ibudilast recruiting a treatment-seeking sample of AUD. Given the limited knowledge about how this class of therapy operates in human samples of AUD and who is most treatment responsive, the proposed study will investigate potential moderators of clinical response and mechanisms of action by leveraging data from this clinical trial of ibudilast. Specifically, Aim #1 tests the hypothesis that facets of negative affect will significantly mediate the relationship between treatment and heavy drinking. Aim #2 tests the hypothesis that peripheral proinflammatory biomarkers and sex will serve as moderators of clinical response to ibudilast. These Aims will be tested using a sophisticated analytic approach including longitudinal multilevel moderation and mediation models. The present study represents an important step in further immune pharmacotherapies for AUD and, with the support of my mentoring team, my scientific development as an independent clinical alcohol researcher with an interest in medications development.