Acid-Sensing Ion Channels in Cardiac Ischemia

心脏缺血中的酸敏感离子通道

• 批准号: 6999365
• 负责人: CHRISTOPHER J BENSON
• 金额: $ 36.01万
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999365
• 关键词: acidity /alkalinity; afferent nerve; amiloride; angina pectoris; biological signal transduction; biosensor device; electrophysiology; gene expression; genetically modified animals; hydrogen ions; immunocytochemistry; ion channel blocker; laboratory mouse; lactates; membrane channels; myocardial ischemia /hypoxia; pathologic process; polymerase chain reaction; protein structure function; sympathetic ganglion; tissue /cell culture; vagus nerve; voltage /patch clamp

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）：在美国大约有 600 万人患有慢性心绞痛，这是一种因冠状动脉疾病引起的心肌缺血引起的疼痛感。 缺血是由感觉（传入）神经元感知的，这些心脏传入神经的激活不仅会导致心绞痛，还会产生交感神经兴奋，这在心肌缺血和梗塞的情况下是有害的。 尽管如此，导致心脏感觉神经元激活的潜在机制仍知之甚少。 我们的目标是检验酸敏离子通道 (ASIC) 是心脏缺血传感器的假设。 这一假设基于先前的研究，该研究表明在心肌缺血的情况下心脏的 pH 值会降低，并且我们的初步数据表明 ASIC 有助于心脏传入神经元中的酸诱发电流。 我们将在三个具体目标上检验这一假设。 具体目标 1 将确定三种 ASIC 蛋白中的哪一种对来自 DRG 和结状神经节的心脏感觉神经元中的酸门控离子通道有贡献。 我们开发了一种在体内特异性标记心脏感觉神经元的方法，以便以后可以在分离的培养物中识别它们。 这将使我们能够识别心脏传入神经中表达的 ASIC，并使用 ASIC 敲除小鼠和异源表达检查它们的功能作用。 具体目标 2 将研究质子和 ASIC 对体内心脏缺血感觉的影响。 我们将测试 ASIC 的药理学和遗传（敲除）破坏是否会改变小鼠模型对心脏酸中毒和缺血的反应。 具体目标 3 将检验以下假设：酸与其他化学介质协同作用以刺激心脏传入，并且它们可能激活会聚的细胞内信号传导机制。 这项工作将为响应心脏缺血的信号和传感器提供新的见解，并确定新的治疗靶点和新的治疗方法。