Acid-sensing and 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。恐慌的神经生物学模型表明，中枢新陈代谢驱动的警报系统功能障碍，并伴随着超敏感的恐惧/焦虑系统。尽管帕金森病的潜在代谢缺陷已被提出，但目前尚不清楚哪些代谢触发因素可能会在脆弱的个体中引发恐慌症发作。最近，酸中毒升高被认为是引发恐慌的主要因素。帕金森病酸碱失衡的观察结果支持了这一点。恐慌症发作通常是由引起pH值失衡的挑战引发的。然而，目前还不清楚pH值中的代谢紊乱如何转化为恐慌和恐惧反应。这种联系对致病的病理生理学至关重要，并可能导致对帕金森病的更特异和有效的治疗。我们最近从啮齿类动物脑中克隆了酸敏感G蛋白偶联受体T细胞死亡相关基因-8(TDAG8)。TDAG8在脑室周围器官(CVO)中占主导地位；最近被发现是惊恐刺激的感应点。重要的是，在TDAG8基因缺陷的小鼠中，与恐慌相关的反应减弱。TDAG8酸感可能提供了一个核心机制来解释恐慌症发作的基础。这项建议的目的是描绘酸敏TDAG8受体和惊恐相关反应之间的机制联系。TDAG8的酸感在恐慌和恐惧反应中的相关性将在三个具体目标下进行测试。目的1确定TDAG8在惊恐原引起的恐惧、焦虑、心血管和呼吸反应表达中的必要性。目的研究TDAG8对细胞酸敏化学感觉反应的调节作用。目的3确定局部酸中毒激活TDAG8是否足以引起惊恐样反应。相关性：TDAG8受体可能为pH代谢紊乱如何转化为恐慌反应提供重要线索。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。

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. Neurobiological models of panic propose a dysfunction in central metabolically driven alarm system coupled with a supersensitive fear/anxiety system. Although an underlying metabolic deficit has been proposed for PD it is currently unclear what metabolic triggers may initiate panic attacks in vulnerable individuals. Recently, elevated acidosis was hypothesized to be a major factor in induction of panic. This is supported by observations of acid-base dysbalance in PD. Panic attacks are often provoked by challenges causing pH imbalance. However, it is not well understood how metabolic disturbances in pH may translate to panic and fear responses. This association is critical to the pathophysiology of panicogenesis and may lead to more specific and effective therapies for PD. We recently cloned acid-sensing G-protein coupled receptor, T cell death associated gene-8 (TDAG8) from rodent brain. TDAG8 is predominant in circumventricular organs (CVOs); recently identified as sensor sites for panic stimuli. Importantly, panic-associated responses are attenuated in TDAG8-deficient mice. TDAG8 acid-sensing may provide a core mechanism to explain the basis of panic attacks. The objective of this proposal is to delineate the mechanistic link between acid-sensing TDAG8 receptor and panic-relevant responses. Relevance of acid-sensing by TDAG8 in panic and fear responses will be tested under three specific aims. Aim 1 To determine the necessity of TDAG8 in the expression of fear, anxiety, cardiovascular and respiratory responses evoked by panicogens. Aim 2 To determine the regulation of cellular acid-sensing chemosensory responses in the CVOs by TDAG8. Aim 3 To determine the sufficiency of local TDAG8 activation by acidosis in the CVOs for inducing panic-like responses. Relevance: The TDAG8 receptor may provide important leads into how metabolic disturbances in pH get translated into panic responses. This association is critical to the pathophysiology of panic and may lead to more specific and effective therapies for PD.