Acid sensing associated mechanisms in AUD and comorbid panic

AUD 和共病恐慌中的酸感应相关机制

• 批准号: 10371655
• 负责人: Katherine Miles Johnston McMurray
• 金额: $ 12.59万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-20 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371655
• 关键词: Abstinence; Acid-Base Imbalance; Acidosis; Acids; Acute; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Anxiety; Attenuated; Behavior; Behavioral; Blood - brain barrier anatomy; Blood Pressure; Brain; Carbon Dioxide; Cardiovascular Physiology; Cardiovascular system; Cell Death; Collection; Complex; Data; Dependence; Development; Disease; Emotional; Emotions; Ethanol; Foundations; Fright; Functional disorder; Genes; Genetic; Goals; Heart Rate; Homeostasis; Hyperventilation; Individual; Inhalation; Lead; Lesion; Mediating; Mental disorders; Methods; Modeling; Molecular; Mus; Neuroimmune; Neuroimmunomodulation; Outcome; Panic; Panic Attack; Panic Disorder; Pathology; Patient-Focused Outcomes; Patients; Phase; Physiological; Physiology; Plethysmography; Positioning Attribute; Predisposition; Publishing; Research; Respiration; Rodent; Role; Severities; Signal Transduction; Stress; Subfornical Organ; T-Lymphocyte; Telemetry; Testing; Time; Training; Treatment outcome; Up-Regulation; Viral; Withdrawal; alcohol comorbidity; alcohol effect; alcohol use disorder; awake; base; binge drinking; cardiovascular effects; career; chronic alcohol ingestion; comorbidity; deter alcohol use; drinking; heart rate variability; improved; knock-down; mouse model; neural circuit; neuroinflammation; new therapeutic target; novel; promoter; psychiatric comorbidity; respiratory; response; sensor

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.

项目概要/摘要 酒精对身体的影响很复杂，会改变行为、情绪和生理。 它们还促进酒精使用和滥用的循环，从而导致酒精使用障碍 (AUD)。 导致合并精神疾病的发生，例如常见的恐慌症 (PD)。 合并症与较差的患者预后相关，但其病理生理学知之甚少 新出现的证据支持酸碱稳态失调可能是一个共同的问题。 AUD 和 PD 中的机制维持生理稳态（例如中性 pH）对于生存至关重要，并且 对体内平衡的威胁会引发针对这一目标的行为、情感和生理反应。 饮酒会引起酸中毒，这与戒断严重程度呈正相关。 PD 中的酸感应失调，但其在 AUD 中的作用尚不清楚，我们的实验室最近发现了一种作用。 新型小胶质细胞酸传感器 T 细胞死亡相关基因 8 (TDAG8) 在恐慌相关行为中的作用 提示性的初步数据显示乙醇会增加 TDAG8 启动子驱动的 GFP 表达。 因此，TDAG8 和相关的神经免疫效应物以 TDAG8 依赖性方式发挥作用。 可以为 AUD 和 PD 提供一种独特且新颖的共享机制。此 K99-R00 提案的目的是。 确定 TDAG8 是否调节 AUD 相关结果（K99 阶段）并有助于发展 共病 AUD-PD（R00 期）。我发表的初步数据支持小胶质细胞的假设。 TDAG8 调节行为（乙醇消耗）和生理（呼吸/心血管）反应 与饮酒有关 (K99)，乙醇引起的 TDAG8 上调会增加对酒精的易感性 开发共病 AUD-PD（R00 期）Aim1（K99 期）将测试小胶质细胞酸传感器的假设。 TDAG8 调节“黑暗饮酒”(DID) 自愿酗酒模型中的乙醇消耗量，目标 2。 （K99阶段）将检验TDAG8介导心血管（血压、心率、心律失常）的假设 率变异性）以及饮酒和戒断（急性和长期戒酒）对呼吸系统的影响。 （R00 阶段）将检验酒精依赖会增加与恐慌相关的行为和行为的假设 以 TDAG8 依赖性方式对 CO2 吸入的生理反应（PD 相关的稳态应激）。 每个目标还将研究神经炎症。这些目标将阐明 AUD 和的机制。 通过关注共同的生理和病理特征来研究 AUD 和 PD 的交叉点。 神经免疫机制将进一步加深我们对每种疾病的理解并带来新的治疗方法。 K99/R00 提案将提供 AUD 小鼠模型的培训、量化神经炎症的方法、 此外，它将提供专业发展，从而促进生理结果的收集/分析。 促进我向独立学术研究职位的过渡，这些目标将为我奠定基础。 研究 AUD 和 PD 等共病疾病的病理生理学的成功独立职业。