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

基本信息

批准号：
8660352
负责人：
KLAUS VAN LEYEN
金额：
$ 37.68万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
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/8660352
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

项目摘要

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）：缺血性脑损伤是心力衰竭后导致高残疾率和死亡率的主要因素。心脏骤停导致海马体和皮质的选择性细胞死亡，以及血管渗漏和水肿。氧化应激是缺血性脑损伤的主要特征，12/15-脂氧合酶（12/15-LOX）是其主要介质之一。在本提案中，我们计划研究 12/15-LOX 对心脏骤停引起的全身缺血后血管损伤和神经元细胞死亡的影响。我们之前已经确定 12/15-LOX 是短暂性局灶性缺血后延迟性神经细胞死亡和血脑屏障渗漏的主要因素。此外，我们还阐明了以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和全脑缺血的小鼠模型来研究心脏骤停后 12/15-LOX 表达的增加。我们的中心假设指出，血管和神经元 12/15-LOX 增加会引起氧化应激，从而导致血管渗漏、水肿和神经元死亡，从而加剧脑损伤。我们的初步结果表明：a) 心脏骤停和复苏小鼠模型中 12/15-LOX 的表达增加； b) 12/15-LOX 与氧化应激标记物 MDA2 以及细胞损伤标记物 FluoroJade B 共定位； c) 这些发现可以在全脑缺血模型中复制； d) 12/15-LOX 基因被删除的小鼠在心脏骤停后表现出较少的损伤。我们建议按照以下具体目标研究 12/15-LOX 上调在小鼠全身缺血模型中的后果。在目标 1 中，我们描述了心脏骤停复苏小鼠模型中 12/15-LOX 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记物。此外，我们将测量水肿和血管渗漏的水平。在目标 2 中，我们研究了通过 12/15-LOX 基因敲除对心脏骤停和复苏小鼠模型中神经细胞死亡和水肿形成的保护作用。在目标 3 中，我们研究了用特定抑制剂在药理学上抑制 12/15-LOX 的保护潜力，并与低温治疗进行比较。我们将使用行为测试和组织学测量来确定短期和长期结果。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 在介导缺血性损伤中的作用可能会为治疗心脏骤停患者带来新的治疗选择。