Acid-sensing and Panic

酸感和恐慌

基本信息

批准号：
8960948
负责人：
RENU SAH
金额：
$ 39.25万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-10 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8960948
关键词：
Acid-Base Imbalance Acidosis Acids Anxiety Anxiety Disorders Area Attenuated Behavioral Bicarbonates Blood - brain barrier anatomy Brain Carbon Dioxide Cardiovascular system Cell Death Cholecystokinin Clinical Clinical Research Complex Coupled Cyclic AMP Development Doxapram Electrophysiology (science)Exhibits Fright Functional disorder G-Protein-Coupled Receptors Genes Hyperventilation Image Individual Intervention Knockout Mice Knowledge Lactic acid Lead Life Link Maps Measures Mental disorders Metabolic Modeling Molecular Mus Neural Pathways Neurobiology Organ Outcome Panic Panic Attack Panic Disorder Pathway interactions Patients Phosphorus Physiological Plethysmography Prevalence Protons Reporting Research Rodent Role Sensory Signal Transduction Site Slice Sodium Lactate Stimulus Structure of area postrema Subfornical Organ System T-Lymphocyte Testing Time Translating base behavior measurement behavioral response cell growth regulation effective therapy novel organum vasculosum of the lamina terminalis receptor resilience respiratory response sensor therapeutic target

项目摘要

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.

描述（由申请人提供）：恐慌症（PD）是一种常见的精神病，每年在美国每年约600万人。尽管进行了大量研究，但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央代谢驱动的警报系统的功能障碍，并具有超敏感的恐惧/焦虑系统。尽管已经提出了针对PD的潜在代谢赤字，但目前尚不清楚哪些代谢触发者可能会引发弱势群体的惊恐发作。最近，假设酸中毒升高是恐慌诱导的主要因素。 PD中酸碱功能障碍的观察结果支持了这一点。恐慌发作通常受到导致pH失衡的挑战引起的。但是，尚不清楚pH中的代谢障碍如何转化为恐慌和恐惧反应。该关联对周期生成的病理生理至关重要，并且可能导致PD的更具体和有效的疗法。我们最近克隆了酸性G蛋白偶联受体，T细胞死亡相关的基因-8（TDAG8）来自啮齿动物脑。 TDAG8在外脑器官（CVO）中占主导地位；最近被确定为恐慌刺激的传感器位点。重要的是，在TDAG8缺陷型小鼠中会减弱恐慌相关的反应。 TDAG8酸性敏感性可以提供一种核心机制来解释恐慌发作的基础。该提案的目的是描述酸敏感的TDAG8受体与恐慌反应之间的机械联系。 TDAG8在恐慌和恐惧反应中对酸性感应的相关性将在三个特定目的下进行测试。目标1确定TDAG8在表达恐惧，焦虑，心血管和呼吸反应中的必要性。 AIM 2确定TDAG8中CVO中细胞酸的化学强度响应的调节。 AIM 3确定酸中毒在CVO中激活局部TDAG8的充分性，以诱导恐慌样反应。相关性：TDAG8受体可能会为pH中的代谢障碍如何转化为恐慌反应的重要线索。该关联对恐慌的病理生理至关重要，可能会导致PD更具体和有效的疗法。