Acid sensing associated mechanisms in AUD and comorbid panic

项目总结/摘要 酒精对身体的影响是复杂的，改变行为，情绪和生理。所有这些影响 导致酒精使用和滥用的循环，导致酒精使用障碍（AUD）。他们还 有助于发展共病精神障碍，如恐慌症（PD），这是常见的。 合并症与更差的患者结局相关，但关于其病理生理学知之甚少。 调节共混物。新出现的证据支持失调的酸碱平衡可能是一个共同的 AUD和PD的机制。维持生理稳态（如中性pH值）对生存至关重要， 对内稳态的威胁会引发针对该目标的行为、情感和生理反应。 酒精使用会导致酸中毒，这与戒断严重程度呈正相关。有力的证据支持 PD中的酸敏感失调，但其在AUDs中的作用尚不清楚。我们的实验室最近发现了 新的小胶质细胞酸传感器T细胞死亡相关基因8（TDAG 8）在恐慌相关行为中的作用， physiology.有趣的是，初步数据显示乙醇增加TDAG 8启动子驱动的GFP表达， 和神经炎症。因此，TDAG 8和相关的神经免疫效应物 可以为AUD和PD提供独特且新颖的共享机制。本K99-R 00提案的目的是 确定TDAG 8是否调节AUD相关结局（K99阶段）并有助于开发 合并AUD-PD（R 00期）。我发表的和初步的数据支持小胶质细胞 TDAG 8调节行为（乙醇消耗）和生理（呼吸/心血管）反应 与酒精使用（K99）相关，并且乙醇诱发的TDAG 8上调增加了对 发生AUD-PD共病（R 00期）。Aim 1（K99期）将检验小胶质细胞酸敏感器 TDAG 8调节“在黑暗中饮酒”（DID）自愿狂欢饮酒模型中的乙醇消耗。目的2 (K99阶段）将检验TDAG 8介导心血管（血压、心率、心脏收缩）的假设。 心率变异性）和酒精使用和戒断（急性和长期戒酒）的呼吸影响。目标3 (R00阶段）将检验酒精依赖会增加恐慌相关行为和 以TDAG 8依赖性方式对CO2吸入的生理反应（PD相关稳态应激）。 每个目标还将研究神经炎症。这些目标将阐明AUDs的机制， 与PD相同。研究AUD和PD的交叉点，重点关注共同的生理和 神经免疫机制将进一步加深我们对每种疾病的理解，并导致新的治疗方法。这 K99/R 00提案将提供AUD小鼠模型的培训，量化神经炎症的方法， 以及生理结果的收集/分析。此外，它将提供专业发展， 帮助我过渡到一个独立的学术研究职位。这些目标将为 一个成功的独立职业生涯，研究AUD和PD等共病疾病的病理生理学。

Project Summary/Abstract Alcohol’s effects on the body are complex, altering behaviors, emotions and physiology. These effects all contribute to the cycle of alcohol use and abuse that leads to alcohol use disorders (AUDs). They also contribute to the development of comorbid psychiatric disorders, like panic disorder (PD), which are common. Comorbidity is associated with worse patient outcomes, yet little is known regarding the pathophysiology regulating comorbidity. Emerging evidence supports dysregulated acid-base homeostasis may be a shared mechanism in AUD and PD. Maintaining physiological homeostasis (e.g. neutral pH) is critical for survival, and threats to homeostasis elicit behavioral, emotional and physiological responses directed toward this goal. Alcohol use induces acidosis which is positively correlated with withdrawal severity. Strong evidence supports dysregulated acid-sensing in PD, but its role in AUDs is not well understood. Our lab recently found a role for a novel microglial acid-sensor T-cell death associated gene 8 (TDAG8) in panic-relevant behavior and physiology. Interestingly, preliminary data show ethanol increases TDAG8-promoter driven GFP expression and neuroinflammation in a TDAG8 dependent manner. Thus, TDAG8 and associated neuroimmune effectors may provide a unique and novel shared mechanism for AUD and PD. The purpose of this K99-R00 proposal is to determine if TDAG8 regulates AUD-associated outcomes (K99 phase) and contributes to development of comorbid AUD-PD (R00 phase). My published and preliminary data support the hypothesis that microglial TDAG8 regulates behaviors (ethanol consumption) and physiological (respiratory/cardiovascular) responses associated with alcohol use (K99), and that ethanol-evoked upregulation of TDAG8 increases susceptibility to develop comorbid AUD-PD (R00 phase). Aim1 (K99 phase) will test the hypothesis that microglial acid-sensor TDAG8 regulates ethanol consumption in the “drinking in the dark” (DID) voluntary binge drinking model. Aim 2 (K99 phase) will test the hypothesis that TDAG8 mediates cardiovascular (blood pressure, heart rate, heart rate variability) and respiratory effects of alcohol use and withdrawal (acute and protracted abstinence). Aim 3 (R00 Phase) will test the hypothesis that alcohol dependence will increase panic-relevant behavioral and physiological responses to CO2 inhalation (PD-relevant homeostatic stress) in a TDAG8-dependent manner. Each aim will also investigate neuroinflammation. These aims will elucidate mechanisms of AUDs and comorbidity with PD. Investigating the intersection of AUD and PD by focusing on shared physiological and neuroimmune mechanisms will further our understanding of each disorder and lead to novel treatments. This K99/R00 proposal will provide training in mouse models of AUDs, methods for quantifying neuroinflammation, and collection/analysis of physiological outcomes. Additionally, it will provide professional development that will facilitate my transition to an independent academic research position. These aims will provide a foundation for a successful independent career investigating pathophysiology of AUD and comorbid disorders like PD.