Role of novel pH-sensing receptor TDAG8 in panic

描述（由申请人提供）：恐慌症（PD）是一种常见的精神疾病，在美国每年大约有600万人患有这种疾病。尽管进行了大量的研究，但PD的神经生物学基础尚不清楚。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。一贯地，惊恐障碍患者对过度通气和乳酸钠输注表现出夸张的乳酸反应，导致极度恐惧和恐慌。这反映了大脑pH值反应和调节的紊乱。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联是重要的，但尚未得到很好的理解。我们最近从啮齿动物的大脑杏仁核中克隆了一个pH感应g蛋白偶联受体——T细胞死亡相关基因-8 （TDAG8）。在调节恐惧和焦虑的区域存在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应用的总体目标是证明TDAG8受体与ph诱导的杏仁核信号传导和恐慌相关行为有关。我们的假设是基于几项观察。首先，TDAG8主要在杏仁核中表达，这是一个与恐惧和恐慌产生有关的区域。其次，酸中毒（H+升高）激活TDAG8，导致钙和pCREB升高，表明TDAG8信号可能对PD中观察到的酸碱失衡敏感。第三，大脑杏仁核中的TDAG8受缺氧的调控，这在生理上与PD相关。TDAG8在杏仁核信号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：确定抑制TDAG8表达是否会影响杏仁核神经元中酸诱发的信号传导。目的2：确定TDAG8缺陷小鼠对致恐慌刺激诱导的恐慌和恐惧反应是否表现出弹性。相关性：TDAG8受体可能为酸碱失调和恐慌和恐惧的表达提供重要线索。这种关联对恐慌的病理生理至关重要，并可能导致PD的更具体和有效的治疗。我们的数据将成为R01拨款的基础，以调查TDAG8与恐慌障碍的相关性。公共卫生相关性：惊恐障碍（PD）是一种常见和复杂的焦虑症，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，目前尚无针对PD的具体治疗方法。酸碱平衡紊乱和恐惧调节异常是其主要原因，但两者之间的确切联系尚不清楚。本研究首次探讨了一种新的脑pH感应受体——T细胞死亡相关基因8 （TDAG8）在恐慌和恐惧中的作用。我们的研究将提高对帕金森病的认识，并改进治疗方法。

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.