The mechanisms of selective cell death after ischemia

缺血后选择性细胞死亡的机制

• 批准号: 7979688
• 负责人: ZAO C XU
• 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: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7979688
• 关键词: Animals; Brain Injuries; Cause of Death; Cell Death; Cerebral Ischemia; Cessation of life; Corpus striatum structure; Dependovirus; Developed Countries; Genetic; Glucose; Glutamates; Heart Arrest; Hippocampus (Brain); In Vitro; Interneurons; Ischemia; Membrane; Neuronal Injury; Neurons; Oxygen; Patients; Pharmacologic Substance; Play; Potassium; Potassium Channel; Property; Public Health; Resistance; Resuscitation; Role; Stroke; Synaptic Transmission; Techniques; Testing; Transgenic Mice; Transient Cerebral Ischemia; United States; deprivation; design; excitotoxicity; hippocampal pyramidal neuron; in vivo; neuronal excitability; neuronal survival; neuroprotection; novel; patch clamp; public health relevance; research study

DESCRIPTION (provided by applicant): Stroke is the leading cause of death in the United States. Cerebral ischemia contributes to more than 80% of the stoke cases. One of the intriguing features of neuronal injury following transient cerebral ischemia is the selective cell death. CA1 pyramidal neurons in the hippocampus and medium spiny (MS) neurons in the striatum die after ischemia whereas the interneurons in the same region remain intact. The objective of this proposal is to reveal a novel mechanism that contributes to the selective cell death following transient cerebral ischemia. Excitotoxicity is a major cause of neuronal death after ischemia. The difference in neuronal excitability between the ischemia-vulnerable and ischemia-resistant neurons might be responsible to the selective cell death. Potassium currents play important roles in regulating neuronal excitability and therefore might contribute to the selective cell death after ischemia. Recent studies have shown that the A-type potassium current is significantly increased in ischemia-resistant neurons after ischemia but remains unchanged in ischemia-vulnerable neurons. We hypothesize that the alteration of A-type potassium current contributes to selective neuronal damage after ischemia. Medium spiny neurons in the striatum die in 24 hr after transient global ischemia while the large aspiny interneurons survive the same insult. Using striatal neurons, the experiments in this proposal are designed to test this novel hypothesis of selective cell death after ischemia. The viability of MS neurons in culture after oxygen-glucose deprivation (OGD) will be compared between neurons with or without over- expression of A-type potassium channel subunits (Kv1.4 and Kv4.2). Furthermore, the viability of neurons after blocking the A-type potassium current with pharmacological agents will be compared with that of control ones after OGD. Then the viability of striatal neurons in animals after over-expression of Kv1.4 and Kv4.2 using adeno-associated virus technique will be compared with that of naove ones after ischemia. The neuronal damage after ischemia will also be compared between the wild-type and transgenic mice lacking Kv1.4 and Kv4.2 subunits after ischemia. The proposed experiments will establish the causal relation of A-type potassium current in selective cell death and reveal a novel mechanism of neuroprotection against ischemia. The results of these studies will provide a new direction for developing pharmaceutical agents, such as A-type potassium channel activator/opener, for patients suffered from cardiac arrest upon resuscitation. PUBLIC HEALTH RELEVANCE: This proposal is relevant to public health concerns because it investigate the mechanisms of brain damage after stroke. The results of these studies will help to develop treatments for stroke patients.

描述（由申请人提供）：中风是美国死亡的主要原因。脑缺血造成了80％以上的Stoke病例。瞬时脑缺血后神经元损伤的有趣特征之一是选择性细胞死亡。在缺血后，海马中的CA1锥体神经元和纹状体死亡的中刺神经元（MS）神经元，而同一区域的中间神经元保持完整。该提案的目的是揭示一种新的机制，该机制有助于瞬时脑缺血后选择性细胞死亡。兴奋性毒性是缺血后神经元死亡的主要原因。缺血性和抗缺血性神经元之间神经元兴奋性的差异可能是选择性细胞死亡的原因。钾电流在调节神经元兴奋性方面起着重要作用，因此可能导致缺血后的选择性细胞死亡。最近的研究表明，缺血性缺血性神经元的A型钾电流显着增加，但在缺血性溶性神经元中保持不变。我们假设A型钾电流的改变会导致缺血后选择性神经元损伤。短暂的全球缺血后24小时内的中等棘神经元死亡，而大的阿斯皮尼中间神经元则在同一侮辱中幸存下来。使用纹状体神经元，该提案中的实验旨在检验缺血后选择性细胞死亡的新假设。在氧气 - 葡萄糖剥夺（OGD）后，MS神经元在培养物中的生存力将在具有或不表达A型钾通道亚基（KV1.4和KV4.2）的神经元之间比较。此外，将神经元与药理学剂阻断A型钾电流后的生存能力将与OGD后对照剂的生存能力进行比较。然后，使用腺相关病毒技术过度表达Kv1.4和Kv4.2后，动物中纹状体神经元的生存力将与缺血后的NAOVE相关的病毒技术进行比较。在缺血后缺乏KV1.4和KV4.2亚基的野生型和转基因小鼠之间，缺血后的神经元损伤也将进行比较。 所提出的实验将建立选择性细胞死亡中A型钾电流的因果关系，并揭示出针对缺血的新型神经保护机制。这些研究的结果将为开发药物剂（例如A型钾通道激活剂/开瓶器）提供一个新的方向，适用于复苏后心脏骤停的患者。 公共卫生相关性：该提案与公共卫生问题有关，因为它调查了中风后脑损伤的机制。这些研究的结果将有助于开发中风患者的治疗方法。