Neuropeptide Modulation of ASICs

描述（由申请人提供）：在美国，由于疾病或损伤引起的获得性脑损伤是导致死亡和残疾的主要原因。然而，一旦发生最初的损伤，几乎没有预防脑损伤和神经元死亡的治疗方法。众所周知，在许多情况下，脑组织会变得异常酸性，导致脑损伤，包括中风、炎症、癫痫发作、创伤性脑损伤（头部创伤）和感染。最近的研究表明，靶向酸感应离子通道1a （ASIC1a）的药物可以预防脑缺血和中风小鼠模型中的神经元死亡。我的实验室对了解ASIC1a如何促进酸中毒诱导的神经元损伤感兴趣。最近，我们发现dynorphins可以阻止ASIC1a脱敏。这些多肽丰富，在生理或病理生理浓度下调节ASIC1a活性。在本提案中，我们将(1)确定dynorphin如何调节ASIC1a活性，(2)测试限制这种相互作用的策略，以及(3)确定dynorphin调节对酸中毒诱导的神经元死亡的影响。我们的初步数据表明，人ASIC1a的反应与小鼠ASIC1a不同。我们将使用只表达人ASIC1a的转基因小鼠系来确定表达人ASIC1a的神经元中神经元死亡和运动啡调节的差异。为了实现这些目标，我们将使用电生理学来分析ASIC1a的活性，并使用细胞生物学方法来评估神经元死亡。这些发现将为asic1诱导的神经元死亡提供基本的见解。由于细胞外酸中毒发生在多种类型的中枢神经系统损伤中，这些发现可能会影响我们对多种损伤模式下神经元死亡的理解。公共卫生相关性：酸中毒伴随中风和缺血导致神经元死亡，在很大程度上是通过激活酸感应离子通道1a （ASIC1a）。拟议的研究将分析ASIC1a的神经肽调节，并确定调节如何影响ASIC激活和酸中毒诱导的神经元死亡的核心特征。ASIC1a代表了治疗预防脑损伤的一个令人兴奋的新靶点，这些研究将为了解ASIC1a诱导的神经元死亡的基本机制提供重要信息。

DESCRIPTION (provided by applicant): Acquired damage to the brain, due to illness or injury, is a leading cause of death and disability in the United States. Yet, there are few treatments for the prevention of brain damage and neuronal death once the initial insults have occurred. It is well recognized that brain tissue becomes abnormally acidic during many conditions that cause brain damage, including stroke, inflammation, seizures, traumatic brain injury (head trauma), and infection. Recent work indicates that agents targeting the Acid-Sensing Ion Channel 1a (ASIC1a) can prevent neuronal death in mouse models of brain ischemia and stroke. My laboratory is interested in understanding how ASIC1a contributes to acidosis-induced neuronal damage. Recently, we discovered that dynorphins prevent ASIC1a desensitization. These peptides are abundant and modulate ASIC1a activity at physiological or pathophysiological concentrations. In this proposal, we will (1) determine how dynorphins modulate ASIC1a activity, (2) test strategies to limit this interaction and (3) determine the effect of dynorphin modulation on acidosis-induced neuronal death. Our preliminary data indicate that the response of human ASIC1a is different from mouse ASIC1a. We will use a transgenic mouse line that expresses human ASIC1a exclusively to determine how neuronal death and dynorphin modulation are different in neurons expressing human ASIC1a. To accomplish these goals we will use electrophysiology to analyze ASIC1a activity and cell biology methods to assess neuronal death. These findings will provide fundamental insight into ASIC1a-induced neuronal mortality. Because extracellular acidosis occurs during many types of injuries to the central nervous system these findings may impact our understanding of neuronal death in multiple injury paradigms. The Public Health Relevance: The acidosis that accompanies stroke and ischemia causes neuronal death, in large-part, by activating the acid-sensing ion channel 1a (ASIC1a). The proposed studies will analyze neuropeptide modulation of ASIC1a and determine how modulation affects characteristics central to ASIC activation and acidosis- induced neuronal death. ASIC1a represents an exciting new target for therapeutics to prevent brain injury and these studies will provide vital information to understand the fundamental mechanism of ASIC1a-induced neuronal death.