Role of novel pH-sensing receptor TDAG8 in panic

新型 pH 传感受体 TDAG8 在恐慌中的作用

• 批准号: 7449113
• 负责人: RENU SAH
• 金额: $ 20.5万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7449113
• 关键词: Acid-Base Equilibrium; Acidosis; Acids; Acute; Address; Affect; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Behavior; Brain; Calcium; Cell Death; Chronic; Cloning; Complex; Data; Diagnosis; Doxapram; Elevation; Equilibrium; Fright; Functional disorder; Future; G-Protein-Coupled Receptors; Genes; Goals; Grant; Health; Hyperventilation; Hypoxia; Infusion procedures; Injection of therapeutic agent; Knowledge; Lactic acid; Lead; Life; Metabolic; Modeling; Mus; Neurobiology; Neurons; Outcome; Panic; Panic Attack; Panic Disorder; Pathogenesis; Patients; Physiological; Physiology; Prevalence; Public Health; Regulation; Research; Rodent; Role; Saline; Signal Transduction; Sodium Lactate; Stimulus; System; T-Lymphocyte; Testing; Therapeutic; Time; Translating; Wild Type Mouse; Work; base; concept; conditioned fear; improved; innovation; novel; novel strategies; psychologic; receptor; resilience; response; sensor

DESCRIPTION (provided by applicant): Panic Disorder (PD) is a common psychiatric illness that afflicts approximately 6 million people annually in the US. Despite considerable research, the neurobiological basis of PD is poorly understood. Most neurobiological models of panic disorder propose two contrasting mechanisms of vulnerability: a) a dysfunction in central metabolically driven alarm system, or b) a supersensitive fear/anxiety system. Consistently, panic disorder patients show an exaggerated lactic acid response to hyperventilation and sodium lactate infusion leading to extreme fear and panic. This reflects a disturbance in the brain pH response and regulation. The interplay between pH regulatory and fear/anxiety systems and their association with panic and fear is important, but not well understood. We have recently cloned a pH sensing G-protein coupled receptor, T cell death associated gene-8 (TDAG8) from rodent brain amygdala. Presence of a pH sensor in a region regulating fear and anxiety is a novel finding that can provide important leads into the mechanisms underlying panic attacks and associated fear. The overall objective of this R-21 application is to prove the concept that the TDAG8 receptor is relevant for pH-induced amygdalar signaling and panic-associated behavior. Our hypothesis is based on several observations. Firstly, TDAG8 is predominantly expressed in the amygdala, a region implicated in the genesis of fear and panic. Secondly, acidosis (rise in H+) activates TDAG8, leading to an elevation of calcium and pCREB, indicating that TDAG8 signaling may be sensitive to acid-base dys-balance which is observed in PD. Thirdly, brain TDAG8 in the amygdala is regulated by hypoxia which is physiologically relevant to PD. Relevance of TDAG8 in amygdalar signaling as well as panic and fear responses will be tested under two specific aims. Aim 1 To determine whether inhibition of TDAG8 expression impacts acid-evoked signaling in amygdalar neurons and Aim 2 Determine whether TDAG8-deficient mice show resilience to panicogenic stimuli induced panic and fear responses. Relevance: The TDAG8 receptor may provide important leads into acid-base dysregulation and the expression of panic and fear. This association is critical to the pathophysiology of panic and may lead to more specific and effective therapies for PD. Our data will form the basis for a R01 grant to investigate the relevance of TDAG8 in panic disorder. PUBLIC HEALTH RELEVANCE: Panic Disorder (PD) is a common and complex anxiety disorder with a life time prevalence of up to 4%. Specific treatments for PD are not available due to a poor understanding of how panic attacks are induced and translated into chronic fear and anxiety. Disturbance in acid-base balance and abnormality in fear regulation are responsible, however, their exact association is not known. This proposal investigates for the first time, the role of a novel brain pH sensing receptor, the T cell death associated gene 8 (TDAG8) in panic and fear. Our studies will improve the understanding of PD and lead to improved treatments.

描述（由申请人提供）：惊恐障碍（PD）是一种常见的精神疾病，在美国每年约有600万人受到折磨。尽管有大量的研究，PD的神经生物学基础知之甚少。大多数惊恐障碍的神经生物学模型提出了两种截然不同的脆弱性机制：a）中枢代谢驱动的警报系统功能障碍，或B）超敏感的恐惧/焦虑系统。同时，惊恐障碍患者对过度通气和乳酸钠输注表现出过度的乳酸反应，导致极度恐惧和惊恐。这反映了大脑pH反应和调节的紊乱。pH调节和恐惧/焦虑系统之间的相互作用及其与恐慌和恐惧的关系很重要，但尚未得到很好的理解。我们最近从啮齿动物脑杏仁核中克隆了一个pH敏感的G蛋白偶联受体，T细胞死亡相关基因8（TDAG 8）。在调节恐惧和焦虑的区域中存在pH传感器是一项新发现，可以为恐慌发作和相关恐惧的潜在机制提供重要线索。这项R-21申请的总体目标是证明TDAG 8受体与pH诱导的杏仁核信号传导和恐慌相关行为相关的概念。我们的假设是基于几个观察。首先，TDAG 8主要在杏仁核中表达，杏仁核是与恐惧和恐慌的发生有关的区域。其次，酸中毒（H+升高）激活TDAG 8，导致钙和pCREB升高，表明TDAG 8信号传导可能对PD中观察到的酸碱失衡敏感。第三，杏仁核中的脑TDAG 8受缺氧调节，这与PD生理相关。TDAG 8在杏仁核信号传导以及恐慌和恐惧反应中的相关性将在两个特定目标下进行测试。目的1确定TDAG 8表达的抑制是否影响杏仁核神经元中的酸诱发信号传导，目的2确定TDAG 8缺陷小鼠是否表现出对惊恐刺激诱导的惊恐和恐惧反应的恢复力。相关性：TDAG 8受体可能为酸碱失衡和恐慌和恐惧的表达提供重要线索。这种关联对惊恐的病理生理学至关重要，并可能导致更特异和有效的PD治疗。我们的数据将成为R 01基金的基础，以调查TDAG 8与惊恐障碍的相关性。公共卫生相关性：惊恐障碍（PD）是一种常见且复杂的焦虑症，终生患病率高达4%。由于对惊恐发作是如何诱发并转化为慢性恐惧和焦虑的理解不足，PD的具体治疗方法不可用。酸碱平衡紊乱和恐惧调节异常是原因，然而，它们的确切联系尚不清楚。该提案首次研究了一种新型脑pH传感受体T细胞死亡相关基因8（TDAG 8）在恐慌和恐惧中的作用。我们的研究将提高对PD的理解，并改善治疗方法。