Acid-sensing and Panic

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。 恐慌的神经生物学模型提出了中枢代谢驱动的警报系统功能障碍，加上超敏感的恐惧/焦虑系统。虽然已经提出了PD的潜在代谢缺陷，但目前尚不清楚哪些代谢触发因素可能会引发脆弱个体的恐慌发作。最近，升高的酸中毒被假设为诱导恐慌的主要因素。这得到了PD中酸碱失衡观察结果的支持。恐慌发作通常是由导致pH不平衡的挑战引起的。然而，目前还不清楚pH值的代谢紊乱如何转化为恐慌和恐惧反应。这种关联对于panicogenesis的病理生理学是至关重要的，并且可能导致更特异和有效的PD治疗。我们最近从啮齿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）。TDAG 8主要存在于室周器官（CVO）中;最近被确定为惊恐刺激的传感器部位。重要的是，恐慌相关反应在TDAG8缺陷型小鼠中减弱。TDAG8酸敏感可能提供了一个核心机制来解释惊恐发作的基础。 本提案的目的是描绘酸敏感TDAG8受体和恐慌相关反应之间的机制联系。将在三个特定目标下测试TDAG8在恐慌和恐惧反应中的酸感的相关性。目的1探讨TDAG 8在惊恐性反应中的作用。目的2探讨TDAG8对CVOs酸敏感化学感受性反应的调节作用。目的3确定CVO酸中毒引起的局部TDAG 8激活是否足以诱导惊恐样反应。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。

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.