Acid-Sensing Ion Channels in Cardiac Ischemia

心脏缺血中的酸敏感离子通道

• 批准号: 7570710
• 负责人: CHRISTOPHER J BENSON
• 金额: $ 34.96万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7570710
• 关键词: ASIC channel; Acidosis; Acids; Address; Afferent Neurons; Amiloride; Buffers; Cardiac; Chemicals; Chronic; Coronary Arteriosclerosis; Cyclic AMP-Dependent Protein Kinases; Data; Esthesia; Ganglia; Gated Ion Channel; Gene Targeting; Genes; Genetic; Goals; Heart; In Vitro; Infarction; Ion Channel Protein; Ischemia; Knock-out; Knockout Mice; Label; Lactic acid; Mediating; Mediator of activation protein; Molecular; Mus; Myocardial; Myocardial Ischemia; Myxoid cyst; Neurons; Nodose Ganglion; Pain; Property; Protons; Reflex action; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensory; Signal Transduction; Testing; Translating; United States; Vascular blood supply; Work; base; immunocytochemistry; in vivo; in vivo Model; insight; mouse model; new therapeutic target; novel strategies; response; sensor

DESCRIPTION (provided by applicant): Approximately 6 million people in the United States suffer from chronic angina, a painful sensation resulting from myocardial ischemia in the setting of coronary artery disease. Ischemia is sensed by sensory (afferent) neurons, and activation of these cardiac afferents leads not only to angina, but also produces sympathoexcitation, which is detrimental in the settings of myocardial ischemia and infarction. Still, the underlying mechanisms that cause activation of cardiac sensory neurons are poorly understood. Our goal is to test the hypothesis that acid-sensing ion channels (ASICs) are sensors of cardiac ischemia. This hypothesis is based on previous work that indicates that pH is reduced in the heart in the setting of myocardial ischemia, and our preliminary data that ASICs contribute to acid-evoked currents in cardiac afferent neurons. We will test this hypothesis in three specific aims. Specific Aim 1 will determine which of the three ASIC proteins contribute to acid-gated ion channels in cardiac sensory neurons from the DRG and nodose ganglia. We have developed a means to specifically label cardiac sensory neurons in vivo so that they can later be identified in isolated culture. This will allow us to identify the ASICs expressed in cardiac afferents, and examine their functional roles using ASIC knockout mice and heterologous expression. Specific Aim 2 will investigate the contribution of protons and ASICs to sensation of cardiac ischemia in vivo. We will test whether pharmacological and genetic (knockouts) disruption of ASICs alters the response to cardiac acidosis and ischemia in a mouse model. Specific Aim 3 will test the hypothesis that acid is working in conjunction with other chemical mediators to excite cardiac afferents, and they may activate convergent intracellular signaling mechanisms. This work will provide new insights into the signals and sensors that respond to cardiac ischemia, and define new therapeutic targets and novel approaches for its treatment.

描述（由申请人提供）：美国约有600万人患有慢性心绞痛，在冠状动脉疾病的情况下，由于心肌缺血引起了痛苦的感觉。 缺血是通过感觉（传入）神经元感知的，这些心脏传入的激活不仅导致心绞痛，而且会产生交感神经兴奋，这在心肌缺血和梗死的情况下是有害的。 尽管如此，引起心脏感觉神经元激活的基本机制还是很少的理解。 我们的目标是检验酸性离子通道（ASIC）是心脏缺血的传感器的假设。 该假设是基于先前的工作，表明在心肌缺血的情况下，心脏中pH降低，而我们的初步数据ASIC有助于心脏传入神经元中的酸诱发的电流。 我们将以三个具体目标来检验这一假设。 具体的目标1将确定三种ASIC蛋白中的哪种有助于DRG和Nodose神经节的心脏感觉神经元中的酸门控离子通道。 我们已经开发了一种在体内特异性标记心脏感觉神经元的方法，以便以后可以在孤立的培养中识别它们。 这将使我们能够识别心脏传入中表达的ASIC，并使用ASIC敲除小鼠和异源表达检查其功能作用。 具体目标2将研究质子和ASIC对体内心脏缺血感觉的贡献。 我们将测试ASIC的药理和遗传（敲除）中断是否会改变小鼠模型中对心脏酸中毒和缺血的反应。 特定的目标3将检验以下假设：酸与其他化学介质共同引起心脏传入，并可能激活收敛的细胞内信号传导机制。 这项工作将为对心脏缺血反应的信号和传感器提供新的见解，并定义了新的治疗靶标和新的治疗方法。