12/15-Lipoxygenase and neurovascular damage following cardiac arrest

心脏骤停后的 12/15-脂氧合酶和神经血管损伤

• 批准号: 8318072
• 负责人: KLAUS VAN LEYEN
• 金额: $ 37.49万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318072
• 关键词: 12-HETE; Address; Affect; Arachidonate 15-Lipoxygenase; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Brain Ischemia; Brain region; Cardiopulmonary Resuscitation; Cell Death; Cerebral Ischemia; Cessation of life; Clinical; Complication; Corpus striatum structure; Coupled; Edema; Event; Extravasation; Goals; Heart Arrest; Heart failure; Hippocampus (Brain); Histopathology; Human; Immunohistochemistry; Impairment; Induced Heart Arrest; Injury; Ischemia; Ischemic Brain Injury; Knockout Mice; Knowledge; Lead; Lipoxygenase Inhibitors; Measures; Mediating; Mediator of activation protein; Modeling; Mus; Nervous System Trauma; Neurologic; Neurologic Examination; Neurological outcome; Neurons; Outcome; Oxidative Stress; Pathway interactions; Patients; Recovery; Reperfusion Injury; Reperfusion Therapy; Resuscitation; Role; Severities; Survivors; Testing; Therapeutic; Time; Up-Regulation; baicalein; behavior test; cell injury; cell type; cohort; disability; dosage; human AMID protein; inhibitor/antagonist; knockout gene; mortality; mouse model; natural hypothermia; neuron loss; neuroprotection; novel strategies; novel therapeutic intervention; novel therapeutics; oxidative damage; research study

DESCRIPTION (provided by applicant): Ischemic brain damage is a major factor contributing to high rates of both disability and mortality following heart failure. Cardiac arrest leads to selective cell death in both hippocampus and cortex, as well as vascular leakage and edema. Oxidative stress is a major feature of ischemic brain damage, and 12/15-lipoxygenase (12/15-LOX) is one of its main mediators. In this proposal, we plan to investigate the contributions of 12/15- LOX to both vascular damage and neuronal cell death following global ischemia induced by cardiac arrest. We have previously established 12/15-LOX as a major contributor to delayed neuronal cell death and leakage of the blood - brain barrier following transient focal ischemia. In addition, we have elucidated a major cell death pathway centered on 12/15-LOX. Here, we will use mouse models of cardiac arrest and global cerebral ischemia to investigate increased 12/15-LOX expression after cardiac arrest. Our central hypothesis states that increased vascular and neuronal 12/15-LOX exacerbates brain damage by causing oxidative stress, leading to vascular leakage, edema, and the death of neurons. Our preliminary results show that a) expression of 12/15-LOX is increased in a mouse model of cardiac arrest and resuscitation; b) 12/15-LOX co-localizes with MDA2, a marker for oxidative stress, as well as FluoroJade B, a marker for cellular injury; c) these findings can be replicated in a model of global cerebral ischemia; and d) mice in which 12/15-LOX has been genetically deleted show reduced damage after cardiac arrest. We propose to study the consequences of 12/15-LOX up-regulation in mouse models of global ischemia in the following specific aims. In Aim 1, we characterize the expression of 12/15-LOX in a mouse model of cardiac arrest with resuscitation. Besides determining the cell types expressing 12/15-LOX, we will investigate markers of oxidative stress and cellular damage. In addition, we will measure levels of edema and vascular leakage. In Aim 2, we study the protection through 12/15-LOX gene knockout against neural cell death and edema formation in the mouse model of cardiac arrest and resuscitation. In Aim 3, we investigate the protective potential of pharmacologically inhibiting 12/15-LOX with a specific inhibitor, and compare with therapeutic hypothermia treatment. We will determine both short- and long-term outcome, using behavioral tests and histological measures. Severe ischemia and reperfusion injury is associated with cardiac arrest and subsequent cardiopulmonary resuscitation. Elucidating the role of 12/15-LOX in mediating ischemic damage may lead to novel therapeutic options in treating cardiac arrest patients.

描述（由申请人提供）：缺血性脑损伤是导致心力衰竭后残疾和死亡率高率的主要因素。心脏骤停导致海马和皮层的选择性细胞死亡，以及血管泄漏和水肿。氧化应激是缺血性脑损伤的主要特征，而12/15-脂氧合酶（12/15-lox）是其主要介体之一。在此提案中，我们计划研究12/15 LOX在心脏骤停引起的全球缺血后，对血管损伤和神经元细胞死亡的贡献。我们以前已经建立了12/15 -LOX，作为延迟神经元细胞死亡和瞬时局灶性缺血后血液屏障的泄漏的主要因素。此外，我们阐明了以12/15-Lox为中心的主要细胞死亡途径。在这里，我们将使用心脏骤停的小鼠模型和全球脑缺血来研究心脏骤停后的12/15-Lox表达。我们的中心假设指出，增加血管和神经元12/15-lox通过引起氧化应激加剧了脑损伤，导致血管渗漏，水肿和神经元死亡。我们的初步结果表明，a）在心脏骤停和复苏的小鼠模型中增加了12/15-Lox的表达； b）12/15-lox与MDA2共定位，MDA2是氧化应激的标记，以及氟体b，是细胞损伤的标记； c）这些发现可以在全球脑缺血模型中复制； D）12/15-lox被遗传删除的小鼠在心脏骤停后显示损害减少。我们建议在以下特定目标中研究全局缺血模型中12/15-LOX上调的后果。在AIM 1中，我们表征了12/15-Lox在复苏的心脏骤停模型中的表达。除了确定表达12/15-lox的细胞类型外，我们还将研究氧化应激和细胞损伤的标志物。此外，我们将测量水肿和血管泄漏的水平。在AIM 2中，我们通过12/15-Lox基因敲除对心脏骤停和复苏的小鼠模型中的神经细胞死亡和水肿形成的保护。在AIM 3中，我们研究了使用特定抑制剂的药理抑制12/15-LOX的保护潜力，并与治疗性低温治疗进行了比较。我们将使用行为测试和组织学指标来确定短期和长期结局。严重的缺血和再灌注损伤与心脏骤停和随后的心肺复苏有关。阐明12/15-lox在介导缺血损伤中的作用可能会导致治疗心脏骤停患者的新型治疗选择。