Investigations into ASIC1a-dependent neuronal death

ASIC1a 依赖性神经元死亡的研究

基本信息

批准号：
10053053
负责人：
CANDICE C ASKWITH
金额：
$ 36.66万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10053053
关键词：
ASIC channel Acidosis Acids Agonist Biochemical Biological Assay Blood flow Brain Brain Injuries Cell Death Cell Line Cerebrum Cessation of life Clinical Co-Immunoprecipitations Collaborations Data Disease Ensure Hour In Vitro Individual Intervention Investigation Ion Channel Ions Ischemia Ischemic Brain Injury Ischemic Stroke Knockout Mice Label Measurement Measures Mediating Methods Middle Cerebral Artery Occlusion Modeling Modification Molecular Profiling Multiple Sclerosis Mus Mutation Nervous System Trauma Neurodegenerative Disorders Neurons Opioid agonist Outcome Pathologic Pharmacology Phosphorylation Phosphorylation Site Physiological Physiology Play Preparation Prevention Proteins Receptor Activation Research Personnel Retinal Degeneration Role Signal Pathway Signal Transduction Slice Spinocerebellar Ataxias Testing Tissues Toxic effect Traumatic Brain Injury Work delta opioid receptor extracellular in vivo injury prevention ischemic injury neuron loss neuroprotection new therapeutic target novel prevent protein protein interaction

项目摘要

The acid sensing ion channel1a (ASIC1a) is essential for normal brain function, but initiates neuronal death and contributes to ischemic brain injury. Prolonged reductions in extracellular pH accompany ischemia and ASIC1a inhibition limits neurological damage. Yet, ASICs also play an important role in normal physiology and established models of ASIC-induced cell death make it difficult to develop strategies that specifically inhibit ASIC1a toxicity. Our preliminary data support a newer model of ASIC1a-induced cell death. Specifically, we have discovered that the toxic effect of ASIC1a can be eliminated by modification of the intracellular region of the channel or activation of the delta opioid receptor (DOR). An especially provocative aspect of these findings is that acidotoxicity is inhibited without a reduction in ASIC1a current, thereby suggesting that the toxic and physiological actions of the channel can be separated. Our central hypothesis is that DOR prevents acidotoxicity through signaling cascades, which act on the intracellular domain of ASIC1a to limit protein interactions required for toxicity. To test this hypothesis, we will define the mechanisms governing DOR action on ASIC1a and elucidate their role in ischemic injury in vivo. The outcomes of the proposed work will reveal novel regulatory mechanisms controlling ASIC1a-induced toxicity, suggest new interventions to mitigate ASIC-induced death using existing DOR agonists, and reveal strategies to separate the physiological and pathological actions of ASIC1a. These results will be significant as they are expected to have broad implications for the prevention of brain injury following ischemic stroke as well as other disorders where neuronal acidotoxicity plays a role.

酸感应离子通道1a（ASIC1A）对于正常脑功能至关重要，但启动神经元死亡并导致缺血性脑损伤。缺血和细胞外pH的长时间减少和 ASIC1A抑制限制了神经系统损害。但是，ASIC在正常生理学和已建立的ASIC诱导的细胞死亡模型使得很难制定专门抑制的策略 ASIC1A毒性。我们的初步数据支持ASIC1A诱导的细胞死亡的较新模型。具体来说，我们已经发现，可以通过修饰细胞内区域来消除ASIC1A的毒性作用三角洲阿片受体（DOR）的通道或激活。这些特别挑衅的方面发现是抑制了酸毒性，而不会降低ASIC1A电流，从而表明通道的有毒和生理作用可以分开。我们的中心假设是DOR阻止通过信号级联反应的酸性毒性，该级数作用于ASIC1A的细胞内结构域以限制蛋白毒性所需的相互作用。为了检验这一假设，我们将定义控制DOR行动的机制在ASIC1A上并阐明其在体内缺血性损伤中的作用。拟议工作的结果将揭示控制ASIC1A诱导的毒性的新型调节机制，建议减轻新的干预措施使用现有的DOR激动剂诱导的ASIC诱导死亡，并揭示了分离生理和 ASIC1A的病理行为。这些结果将很重要，因为它们预计会有广泛缺血性中风后的预防脑损伤以及其他疾病的影响神经元酸毒性起作用。