Investigations into ASIC1a-dependent neuronal death

ASIC1a 依赖性神经元死亡的研究

• 批准号: 10393671
• 负责人: CANDICE C ASKWITH
• 金额: $ 36.47万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10393671
• 关键词: ASIC channel; Acidosis; Acids; Agonist; Biochemical; Biological Assay; Blood flow; Brain; Brain Injuries; Brain Ischemia; Cell Death; Cell Death Induction; Cell Line; Cerebrum; Cessation of life; Clinical; Co-Immunoprecipitations; Collaborations; Data; Disease; 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; 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; pharmacologic; prevent; protein protein interaction

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.

酸敏感离子通道1a（ASIC1a）对正常脑功能至关重要，但会引发神经元死亡 并导致缺血性脑损伤。细胞外pH的长期降低伴随缺血， ASIC1a抑制限制神经损伤。然而，ASIC在正常生理学中也起着重要作用， ASIC诱导的细胞死亡的已建立模型使得难以开发特异性抑制ASIC诱导的细胞死亡的策略。 ASIC1a毒性。我们的初步数据支持ASIC 1a诱导细胞死亡的较新模型。我们特别 已经发现ASIC1a的毒性作用可以通过修饰细胞内区域来消除， δ阿片受体（DOR）的通道或激活。其中一个特别具有挑衅性的方面是， 结果是，酸毒性被抑制，而不减少ASIC1a电流，从而表明， 可以将通道的毒性和生理作用分开。我们的中心假设是DOR阻止了 通过信号级联的酸毒性，其作用于ASIC1a的细胞内结构域以限制蛋白质 毒性所需的相互作用。为了验证这一假设，我们将定义DOR作用的机制 对ASIC1a的影响，并阐明其在体内缺血损伤中的作用。拟议工作的结果将揭示 控制ASIC1a诱导的毒性的新的调节机制，提出了新的干预措施，以减轻 使用现有的DOR激动剂，ASIC诱导的死亡，并揭示了分离生理和 ASIC1a的病理作用。这些结果将是重要的，因为他们预计将有广泛的 对预防缺血性中风后脑损伤以及其他疾病的影响， 神经元酸毒性起作用。

项目成果

In vivo Mouse Intervertebral Disc Degeneration Models and Their Utility as Translational Models of Clinical Discogenic Back Pain: A Comparative Review.

• DOI: 10.3389/fpain.2022.894651
• 发表时间: 2022
• 期刊: Frontiers in pain research (Lausanne, Switzerland)

Sleep fragmentation engages stress-responsive circuitry, enhances inflammation and compromises hippocampal function following traumatic brain injury.

• DOI: 10.1016/j.expneurol.2022.114058
• 发表时间: 2022-07
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Tapp, Zoe M.;Cornelius, Sydney;Oberster, Alexa;Kumar, Julia E.;Atluri, Ravitej;Witcher, Kristina G.;Oliver, Braedan;Bray, Chelsea;Velasquez, John;Zhao, Fangli;Peng, Juan;Sheridan, John;Askwith, Candice;Godbout, Jonathan P.;Kokiko-Cochran, Olga N.
• 通讯作者: Kokiko-Cochran, Olga N.