Stress Granules Cause Translation Arrest In Ischemic Vulunerable Neurons

应激颗粒导致缺血性易损神经元的翻译停滞

• 批准号: 8022879
• 负责人: DONALD J DEGRACIA
• 金额: $ 32.26万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8022879
• 关键词: Address; Antibiotics; Behavior; Biochemical; Blood; Blood flow; Brain; Brain Injuries; Brain Ischemia; Cause of Death; Cell Death; Cells; Cellular Stress; Cessation of life; Clinical; Cytoplasmic Granules; Data; Development; Employee Strikes; Evolution; Foundations; Goals; Heart Arrest; Hippocampus (Brain); Hour; Image; Ischemia; Ischemic Brain Injury; Ischemic Preconditioning; Laboratories; Left; Microscope; Microscopic; Morbidity - disease rate; Neurons; Physicians; Printing; Protein Biosynthesis; Protein Synthesis Inhibition; Protein Synthesis Inhibitors; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Resistance; Resolution; Resuscitation; Scientist; Stress; Stroke; Subcellular structure; Time; Translations; United States National Institutes of Health; Visual; Work; cell injury; effective therapy; hippocampal pyramidal neuron; injured; mortality; neuronal survival; particle; prevent; programs; success

DESCRIPTION (provided by applicant): Ischemia and reperfusion (I/R) injury of the brain occurs following resuscitation from cardiac arrest and stroke, and results in high morbidity and mortality. There is no clinically effective treatment because of an incomplete understanding of the cellular injury cascades leading to cell death. The long- term goal of my laboratory is to investigate the mechanisms of neuronal death caused by brain I/R to allow for the development of effective treatments. There is a striking correlation between protein synthesis inhibition and the selective death of hippocampal CA1 pyramidal neurons following transient global brain I/R. The mechanism of this irreversible translation arrest and its relationship to cell death is unknown. Stress granules are cytoplasmic particles that sequester inactive translational machinery during cellular stress. We present compelling evidence that stress granule alterations are central to persistent translation arrest in ischemic-vulnerable hippocampal CA1 neurons. Our Specific Aims are: 1. To investigate the mechanism of irreversible translation arrest. We will analyze the functional composition of stress granules utilizing complementary microscopic and biochemical approaches. We will compare stress granules in ischemic resistant CA3 and ischemic vulnerable CA1 from early reperfusion to the point of cell death of vulnerable neurons. 2. To identify the effect of ischemic preconditioning (IPC) on stress granule composition and behavior in reperfused neurons. IPC prevents both cell death and persistent translation arrest in vulnerable CA1 neurons. We will assess the effect of IPC on stress granule behavior and composition, protein synthesis rates, and cell death in CA1 neurons. 3. To show that persistent translation arrest is causally related to neuronal death following brain I/R. Antibiotic protein synthesis inhibitors will be used to predictably alter stress granules in reperfused hippocampal neurons, and we will examine the effect on protein synthesis rates, stress granule composition and behavior and cell death in reperfused hippocampal neurons. By providing an integrated examination of the relationship between persistent translation arrest and I/R-induced cell death, our Specific Aims address a problem that has been a barrier to progress in the field: how irreversible inhibition of protein synthesis in reperfused neurons causes cell death. PUBLIC HEATH RELEVANCE: Every year, millions of people are injured or die from brain damage caused by cardiac arrest or stroke. There are no treatments to prevent this brain damage because physicians and scientists do not understand how the cells die following a period when blood has stopped flowing in the brain and subsequently resumed. The work in this proposal seeks to further our understanding of the way in which neurons in the brain die following a period of low or no blood flow (ischemia) followed by resumption of normal blood flow (reperfusion).

描述（由申请人提供）：脑缺血再灌注（I/R）损伤发生在心脏骤停和中风复苏后，导致高发病率和死亡率。由于对导致细胞死亡的细胞损伤级联反应了解不完全，目前尚无临床有效的治疗方法。我的实验室的长期目标是研究脑I/R引起的神经元死亡的机制，以便开发有效的治疗方法。在短暂性脑I/R后，蛋白质合成抑制与海马CA1锥体神经元的选择性死亡之间存在显著相关性。这种不可逆翻译阻滞的机制及其与细胞死亡的关系尚不清楚。应激颗粒是细胞质颗粒，在细胞应激时隔离不活跃的翻译机制。我们提出了令人信服的证据，表明应激颗粒改变是缺血易感海马CA1神经元持续翻译阻滞的核心。我们的具体目标是：1；探讨不可逆翻译阻滞的机制。我们将利用互补的显微镜和生化方法分析应力颗粒的功能组成。我们将比较易损神经元从早期再灌注到细胞死亡时，缺血抵抗CA3和缺血易损CA1中的应激颗粒。2. 探讨缺血预处理（IPC）对再灌注神经元应激颗粒组成和行为的影响。IPC可防止易损CA1神经元的细胞死亡和持续翻译阻滞。我们将评估IPC对CA1神经元应激颗粒行为和组成、蛋白质合成率和细胞死亡的影响。3. 结果表明，持续性翻译阻滞与脑I/R后神经元死亡存在因果关系。抗生素蛋白合成抑制剂将用于可预测地改变再灌注海马神经元中的应激颗粒，我们将研究其对再灌注海马神经元中蛋白质合成速率、应激颗粒组成和行为以及细胞死亡的影响。通过对持续翻译阻滞和I/ r诱导的细胞死亡之间关系的综合研究，我们的特定目标解决了一个一直阻碍该领域进展的问题：再灌注神经元中蛋白质合成的不可逆抑制如何导致细胞死亡。公共卫生相关性：每年有数百万人因心脏骤停或中风造成的脑损伤而受伤或死亡。目前还没有预防这种脑损伤的治疗方法，因为医生和科学家都不明白细胞是如何在大脑血液停止流动一段时间后死亡的，然后又恢复了。本研究旨在进一步了解脑内神经元是如何在一段时间的低血流量或无血流量（缺血）后恢复正常血流量（再灌注）而死亡的。