Neuropeptide Modulation of ASICs

ASIC 的神经肽调节

• 批准号: 7508433
• 负责人: CANDICE C ASKWITH
• 金额: $ 26.25万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7508433
• 关键词: ASIC channel; Acidosis; Acids; Affect; Brain; Brain Injuries; Brain Ischemia; Cause of Death; Cell Death; Cellular biology; Cerebral Ischemia; Cerebrum; Cessation of life; Characteristics; Complex; Condition; Craniocerebral Trauma; Data; Dependence; Dynorphin A; Dynorphins; Electrophysiology (science); Event; Figs - dietary; Fright; Genetic; Goals; Human; Infection; Inflammation; Injury; Ischemia; Knock-out; Laboratories; Laboratory Study; Learning; Mediating; Memory; Methods; Molecular; Multiple Trauma; Mus; Neuraxis; Neurological observations; Neurons; Neuropeptides; Opioid Peptide; Opioid Receptor; Pain; Peptides; Personal Satisfaction; Physiological; Play; Prevention; Process; Public Health; Risk Factors; Role; Seizures; Stroke; Testing; Transgenic Mice; Traumatic Brain Injury; United States; Venoms; Work; acquired brain damage; arginylphenylalaninamide; base; brain tissue; central nervous system injury; desensitization; disability; extracellular; in vivo; insight; interest; mortality; mouse model; outcome forecast; prevent; research study; response; size; therapeutic target

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.

描述(申请人提供)：后天脑损伤，由于疾病或伤害，是美国死亡和残疾的主要原因。然而，在最初的侮辱发生后，几乎没有什么治疗方法可以防止大脑损伤和神经元死亡。众所周知，在许多导致大脑损伤的情况下，脑组织会变得异常酸性，包括中风、炎症、癫痫发作、创伤性脑损伤(头部创伤)和感染。最近的工作表明，针对酸敏离子通道1a(ASIC1a)的药物可以防止小鼠脑缺血和中风模型中的神经元死亡。我的实验室有兴趣了解ASIC1a是如何导致酸中毒诱导的神经元损伤的。最近，我们发现强啡肽可以阻止ASIC1a脱敏。这些多肽含量丰富，在生理或病理生理浓度下调节ASIC1a的活性。在这项提案中，我们将(1)确定强啡肽如何调节ASIC1a的活性，(2)测试限制这种相互作用的策略，以及(3)确定强啡肽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的反应不同于小鼠ASIC1a。我们将使用专门表达人ASIC1a的转基因小鼠来确定神经元死亡和强啡肽调节在表达人ASIC1a的神经元中有何不同。为了实现这些目标，我们将使用电生理学来分析ASIC1a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ASIC1a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中枢神经系统的许多类型的损伤中，这些发现可能会影响我们对多重损伤范例中神经元死亡的理解。与公共卫生相关：伴随中风和缺血的酸中毒在很大程度上通过激活酸敏感离子通道1a(ASIC1a)导致神经元死亡。这项拟议的研究将分析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中心特征。ASIC1a为治疗学预防脑损伤提供了一个令人兴奋的新靶点，这些研究将为理解ASIC1a诱导神经元死亡的基本机制提供重要信息。