A Novel Ionic Mechanism of Ischemic Neuronal Injury

缺血性神经元损伤的新离子机制

• 批准号: 8165223
• 负责人: Ping Deng
• 金额: $ 19.25万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165223
• 关键词: Brain region; Cations; Cause of Death; Cell Death; Cells; Cerebral Ischemia; Cessation of life; Corpus striatum structure; Cyclic AMP; Data; Dependence; Homeostasis; Immunohistochemistry; Interneurons; Ion Channel; Ions; Ischemia; Ischemic Neuronal Injury; Kinetics; Learning; Location; Mediating; Membrane; Movement; Neostriatum; Neuronal Injury; Neurons; Pathologic Processes; Patients; Phosphatidylinositol 4,5-Diphosphate; Phospholipids; Play; Property; Prosencephalon; Protein Isoforms; Proteins; Recovery; Regulation; Resistance; Role; Small Interfering RNA; Specific qualifier value; Stroke; Transient Cerebral Ischemia; Up-Regulation; Western Blotting; Work; cholinergic; cognitive function; density; design; effective therapy; excitotoxicity; improved; in vivo Model; lamotrigine; nervous system disorder; neuronal excitability; neuroprotection; novel; novel strategies; novel therapeutics; overexpression; protein expression; research study; voltage; voltage clamp

DESCRIPTION (provided by applicant): Effective treatment for stroke is limited largely by the fact that the underlying mechanisms of neuronal death caused by cerebral ischemia are still unclear. This proposal will investigate the ionic mechanisms of ischemic neuronal injury. Transient cerebral ischemia causes selective neuronal death in certain brain regions, including the neostriatum, which is fundamental to sensorimotor learning, movement control and cognitive functions. Protecting striatal neurons against ischemia will improve the recovery of striatum-mediated functions after stroke. Studies have shown that increase of neuronal excitability and disruption of intracellular ion homeostasis are critical for neuronal injury after ischemia. Hyperpolarization-activated cation current (Ih) mediates influx of Na+ and K+, and plays critical roles in controlling neuronal excitability. Most of previous studies have focused on the excitotoxicity and depolarization-activated ion channels, and indicate that post-ischemic depolarization may contribute to cell death, and that hyperpolarization may be involved in neuroprotection. However, active Ih during hyperpolarization in striatal neurons may be associated with ischemic neuronal injury. Indeed, we have found that transient forebrain ischemia induces an expression of functional Ih in ischemia-vulnerable spiny neurons in the neostriatum, which is absent under control conditions. Meanwhile, Ih in ischemia-resistant striatal cholinergic interneurons is inhibited after ischemia. Most importantly, our preliminary data have shown that blocking Ih protects striatal neurons against ischemia. We hypothesize that upregulation of functional Ih contributes to ischemic neuronal death in the neostriatum. In this project, experiments are designed to investigate how Ih in striatal neurons is altered after ischemia, what are the underlying mechanisms, and what are the relations of Ih change with ischemic neuronal death. The temporal changes of Ih in striatal neurons following transient forebrain ischemia will be characterized using electrophysiological recording. To investigate the underlying mechanisms of Ih changes, the modulation of Ih by cyclic AMP and membrane phospholipids (PIP2) will be compared before and after ischemia. In addition, alterations of Ih channel interacting proteins (TRIP8b), which profoundly regulate Ih function, will be examined. Finally, the involvement of specific Ih channel subunits will be identified in ischemia in vivo models. This project may provide novel strategies to protect neurons against ischemic insults. PUBLIC HEALTH RELEVANCE: This proposal will identify the cellular mechanisms underlying the post-ischemic changes of Ih in striatal neurons, and the functional significance of Ih in ischemic cell death. An understanding of the cellular mechanisms of neuronal injury has great potential in developing novel therapeutic strategies for stroke patients.

描述(申请人提供)：中风的有效治疗在很大程度上受到这样一个事实的限制，即脑缺血导致神经元死亡的潜在机制仍不清楚。这项建议将探讨缺血性神经元损伤的离子机制。短暂性脑缺血导致特定脑区选择性神经元死亡，包括新纹状体，新纹状体是感觉运动学习、运动控制和认知功能的基础。保护纹状体神经元免受缺血将促进卒中后纹状体介导的功能的恢复。研究表明，神经元兴奋性的增加和细胞内离子稳态的破坏是缺血后神经元损伤的关键。超极化激活的阳离子电流(Ih)介导Na+、K+内流，在控制神经元兴奋性方面起着关键作用。以往的研究大多集中在兴奋性毒性和去极化激活的离子通道上，表明缺血后去极化可能导致细胞死亡，超极化可能参与神经保护。然而，纹状体神经元超极化时激活的Ih可能与缺血性神经元损伤有关。事实上，我们已经发现，短暂性前脑缺血诱导新纹状体中易受缺血影响的棘神经元表达功能性Ih，这在对照条件下是不存在的。同时，缺血后抗缺血纹状体胆碱能中间神经元的Ih受到抑制。最重要的是，我们的初步数据显示，阻断ih可以保护纹状体神经元免受缺血的影响。我们假设功能性Ih的上调有助于新纹状体中的缺血性神经元死亡。本实验旨在研究脑缺血后纹状体神经元Ih的变化，其潜在的机制是什么，以及Ih变化与缺血神经元死亡的关系。短暂性前脑缺血后纹状体神经元ih的时间变化将通过电生理记录来表征。通过比较缺血前后环磷酸腺苷(CAMP)和膜磷脂(PIP2)对缺血缺氧的调节作用，探讨缺血缺氧的可能机制。此外，还将研究深入调节Ih功能的Ih通道相互作用蛋白(TRIP8b)的变化。最后，将在活体缺血模型中确定特定的Ih通道亚单位的参与。该项目可能为保护神经元免受缺血损伤提供新的策略。 公共卫生相关性：这项建议将确定缺血后纹状体神经元ih变化的细胞机制，以及ih在缺血细胞死亡中的功能意义。了解神经元损伤的细胞机制在开发中风患者的新治疗策略方面具有巨大的潜力。