Role of novel pH-sensing receptor TDAG8 in panic

描述(由申请者提供)：恐慌症(PD)是一种常见的精神疾病，每年在美国约有600万人受到困扰。尽管进行了大量研究，但人们对帕金森病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易损性机制：a)中枢新陈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。始终，惊恐障碍患者对过度换气和乳酸钠输注表现出夸大的乳酸反应，导致极度恐惧和恐慌。这反映了大脑pH反应和调节的紊乱。PH值调节和恐惧/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，但还没有被很好地理解。我们最近从啮齿类动物的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(TDAG8)。在调节恐惧和焦虑的区域中存在pH传感器是一项新的发现，可以为研究恐慌症发作和相关恐惧的机制提供重要线索。这项R-21应用的总体目标是证明TDAG8受体与pH诱导的杏仁核信号和惊恐相关行为相关这一概念。我们的假设是基于几个观察结果。首先，TDAG8主要在杏仁核表达，该区域与恐惧和恐慌的起源有关。其次，酸中毒(H+升高)激活TDAG8，导致钙离子和pCREB升高，提示TDAG8信号可能对帕金森病患者的酸碱失衡敏感。第三，大脑杏仁核中的TDAG8受低氧的调节，这与帕金森病有生理上的关系。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表达是否影响杏仁核神经元中酸诱导的信号转导；目的2确定TDAG8基因缺陷小鼠是否表现出对惊恐和恐惧反应的弹性。相关性：TDAG8受体可能会导致酸碱失衡以及恐慌和恐惧的表达。这种联系对恐慌症的病理生理学至关重要，并可能导致对帕金森病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在惊恐障碍中的相关性。公共卫生相关性：恐慌症(PD)是一种常见而复杂的焦虑症，终生患病率高达4%。由于对恐慌症发作是如何诱发并转化为慢性恐惧和焦虑的理解很差，帕金森氏症的具体治疗方法还不可用。酸碱平衡失调和恐惧调节异常是其原因，然而，它们之间的确切联系尚不清楚。这项提议首次研究了一种新的大脑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。我们的研究将提高人们对帕金森病的认识，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.