A novel neuroprotective strategy

一种新颖的神经保护策略

• 批准号: 8278195
• 负责人: Elias Aizenman
• 金额: $ 22.04万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278195
• 关键词: Achievement; Affect; Apoptosis; Apoptotic; Biochemical; Biological; Brain Injuries; Caspase; Cell Death; Cell membrane; Cells; Chronic; Depressed mood; Development; Disease; Ensure; Environment; Future; Generations; Genomics; Goals; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Infection; Infectious Agent; Injury; Investigation; Laboratories; Lead; Liver; MAPK14 gene; Mediating; Methods; Midbrain structure; Nerve Degeneration; Neurons; Neuroprotective Agents; Oxidants; Pathway interactions; Peptide Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Plasmids; Potassium; Potassium Channel; Probability; Process; Proteins; RNA; Recombinants; Research; Role; SNAP receptor; Signal Transduction; Stimulus; Stroke; System; Testing; Translating; Translation Process; Virus; base; body system; design; high reward; high risk; molecular domain; neuron loss; novel; novel therapeutics; nuclease; prevent; programs; prototype; research study; src-Family Kinases; trafficking; treatment strategy; voltage

DESCRIPTION (provided by applicant): This application aims to investigate whether a mechanism used by a virus to block hepatocyte apoptosis can be translated and optimized to block neuronal cell death following injury. Although several signaling cascades responsible for neurodegenerative changes following stroke and related disorders have been well characterized, effective neuroprotective therapies to treat human conditions continue to elude us. Thus, investigations designed to uncover novel neuroprotective strategies, such as those describe here, are potentially of very high significance. Our laboratory is testing the general hypothesis that distinct cell death pathways, triggered by diverse injurious stimuli or composed of unique biochemical signaling cascades, require a set of common conditions to operate optimally. Over the last ten years, we have defined a neuronal pro-apoptotic signaling cascade characterized by a robust enhancement of voltage dependent K+ currents. This phenomenon ensures the completion of cell death programs by providing a venue for the loss of cytoplasmic K+, establishing a permissive environment for protease and nuclease activation. Interfering with the processes responsible for the apoptotic K+ current surge can effectively block neuronal cell death. In mammalian cortical and midbrain neurons, the current surge is mediated by a de novo SNARE-dependent exocytotic insertion of Kv2.1-encoded K+ channels into the cell membrane. Remarkably, a product of the translation and processing of the hepatitis C virus genomic RNA, the non-structural protein 5A (NS5A), was recently shown to effectively interfere with Kv2.1-mediated apoptotic K+ currents in liver cells and inhibit hepatocyte cell death. In preliminary studies we observed that NS5A could also be employed to rescue neurons following injury and that this protein interferes with the neuronal Kv2.1-mediated apoptotic K+ current surge. In this application we intend to (i) investigate the mechanism responsible for NS5A interference with Kv2.1 functional expression, and (ii) define the molecular domains of NS5A necessary for restricting channel function. These latter experiments will establish the minimal NS5A-derived sequences that can be used for the design of novel neuroprotective probes. The overarching goal of our research program is to devise new therapeutic strategies to protect neurons following injury. We are exploring a novel, possibly groundbreaking approach to achieve this goal by constructively harnessing a biological strategy that evolved to block cell death in the liver and translating it towards the generation of novel methods to treat stroke and other forms of neurodegeneration. PUBLIC HEALTH RELEVANCE: The research proposed in this application will help us understand the role of potassium channel function in neuronal cell death. Most importantly, research conducted during this project may reveal novel avenues for developing a new class of neuroprotective drugs to prevent brain damage during stroke and related conditions.

描述（由申请人提供）：本申请旨在研究病毒用于阻断肝细胞凋亡的机制是否可以被翻译和优化，以阻断损伤后的神经元细胞死亡。虽然几个信号级联负责脑卒中和相关疾病后的神经退行性变化已经得到很好的表征，有效的神经保护疗法来治疗人类的条件继续逃避我们。因此，旨在发现新的神经保护策略的研究，如本文所述，可能具有非常高的意义。我们的实验室正在测试的一般假设，不同的细胞死亡途径，由不同的有害刺激触发或独特的生化信号级联组成，需要一组共同的条件下，以最佳的操作。在过去的十年中，我们已经定义了一个神经元促凋亡信号级联，其特征在于电压依赖性K+电流的鲁棒增强。这种现象通过为细胞质K+的损失提供场所，建立蛋白酶和核酸酶活化的容许环境，确保细胞死亡程序的完成。干预导致凋亡性K+电流浪涌的过程可以有效地阻断神经元细胞死亡。在哺乳动物皮层和中脑神经元中，电流浪涌是由Kv2.1编码的K+通道的从头SNARE依赖性胞吐插入细胞膜介导的。值得注意的是，丙型肝炎病毒基因组RNA的翻译和加工产物，即非结构蛋白5A（NS5A），最近被证明可以有效地干扰肝细胞中Kv2.1介导的凋亡K+电流并抑制肝细胞死亡。在初步研究中，我们观察到，NS5A也可以用来拯救神经元损伤后，这种蛋白质干扰神经元Kv2.1介导的凋亡K+电流浪涌。在本申请中，我们打算（i）研究负责NS5A干扰Kv2.1功能表达的机制，以及（ii）定义限制通道功能所必需的NS5A的分子结构域。这些后面的实验将建立可用于设计新的神经保护探针的最小NS5A衍生序列。我们研究计划的总体目标是设计新的治疗策略来保护损伤后的神经元。我们正在探索一种新的，可能是开创性的方法来实现这一目标，通过建设性地利用一种生物学策略来阻止肝脏中的细胞死亡，并将其转化为治疗中风和其他形式的神经退行性疾病的新方法。 公共卫生关系：本申请中提出的研究将有助于我们了解钾通道功能在神经元细胞死亡中的作用。 最重要的是，在该项目期间进行的研究可能揭示开发一类新的神经保护药物的新途径，以防止中风和相关疾病期间的脑损伤。