Acid-sensing and 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。恐慌的神经生物学模型提出中枢代谢驱动的警报系统功能障碍与超敏感的恐惧/焦虑系统相结合。尽管已经提出PD的潜在代谢缺陷，但目前尚不清楚是什么代谢触发因素引发了易感个体的恐慌发作。最近，升高的酸中毒被假设为诱发恐慌的一个主要因素。PD中酸碱失衡的观察结果支持了这一点。恐慌症通常是由pH值失衡引起的。然而，目前尚不清楚pH值的代谢紊乱如何转化为恐慌和恐惧反应。这种关联对帕金森病发生的病理生理学至关重要，并可能导致更特异性和更有效的PD治疗。我们最近从啮齿动物大脑中克隆了酸感g蛋白偶联受体T细胞死亡相关基因-8 （TDAG8）。TDAG8主要存在于心室周围器官（CVOs）；最近被确认为恐慌刺激的感应点。重要的是，tdag8缺陷小鼠的恐慌相关反应减弱。TDAG8酸感可能提供了解释恐慌发作基础的核心机制。本提案的目的是描述酸敏感TDAG8受体和恐慌相关反应之间的机制联系。TDAG8在恐慌和恐惧反应中的酸感相关性将在三个具体目标下进行测试。目的1：探讨TDAG8在致病菌引起的恐惧、焦虑、心血管和呼吸反应表达中的必要性。目的2：探讨TDAG8对CVOs细胞酸感化学感觉反应的调控作用。目的3确定CVOs酸中毒引起的局部TDAG8激活是否足以诱导恐慌样反应。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。

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.