Cyclooxygenase-2 Regulation of Blood-Brain Barrier Opening in Ischemic Stroke

环氧合酶 2 对缺血性中风血脑屏障开放的调节

基本信息

批准号：
8460883
负责人：
Eduardo Jesus Candelario-Jalil
金额：
$ 30.29万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8460883
关键词：
Acute Alteplase Animals Basic Science Biochemical Biological Assay Blood - brain barrier anatomy Brain Brain Ischemia Cells Cerebral Ischemia Cessation of life Coupled Coxibs Data Development Dinoprostone Drug Targeting Edema Event FDA approved Fluorescence Resonance Energy Transfer Foundations Gene Deletion Goals Hospitals Hour Human Immunoblotting Infarction Inflammation Inflammatory Injury Ischemia Ischemic Brain Injury Ischemic Penumbra Ischemic Stroke Knowledge Late Effects Lead Long-Term Effects Longitudinal Studies Magnetic Resonance Imaging Matrix Metalloproteinases Measures Mediating Methods Middle Cerebral Artery Occlusion Mission Modeling Nervous System Physiology Neurologic Neuronal Injury Neurons Pathway interactions Patients Peptides Pharmaceutical Preparations Phase Process Production Public Health Rattus Recovery Regulation Research Role Signal Transduction Stroke Sucrose Tars Techniques Testing Therapeutic Therapeutic Intervention Time Tissues angiogenesis base brain tissue clinically relevant cyclooxygenase 2 expectation human WFDC2 protein improved in vivo innovation nervous system disorder neurogenesis neuroinflammation neuroprotection neutrophil novel novel therapeutics prostanoid receptor EP1 public health relevance receptor repaired research study

项目摘要

DESCRIPTION (provided by applicant): Neuroinflammation leads to progressive damage in ischemic stroke. Disruption of the blood-brain barrier (BBB) occurring at 24-48 h following ischemic stroke is a pathological mechanism that contributes to neuronal death. There is an urgent need to identify pharmacological strategies that limit the secondary damage following stroke. The cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) pathway is actively involved in inflammatory events that exacerbate initial ischemic brain injury. Our long-term goal is to understand how the COX-2/PGE2 pathway can be manipulated to block the progressive injury cascade following ischemic stroke. The overall objective of this project is to determine how increased COX-2/PGE2 mediates BBB damage and neuronal death in ischemic stroke. Our central hypothesis is that inhibition of the COX-2/PGE2 pathway protects against BBB damage and neuronal death by reducing MMP-3/-9 production. The rationale for the proposed research is that understanding the mechanisms involved in acute (deleterious) and late (possibly beneficial) effects of COX-2/PGE2 in stroke should identify novel targets for a more selective and effective therapeutic intervention with drugs blocking the COX-2/PGE2 pathway. Specific Aim #1: To identify the downstream effectors of COX-2-mediated increase in MMP-3/-9 expression/activity and damage to the BBB after ischemia. Experiments in this aim test the hypothesis that COX-2-derived PGE2 induces MMP-3/-9 production and BBB breakdown through activation of specific EP receptor(s) in focal ischemic brain injury. We will utilize an in vivo pharmacological approach in a well- established rat model of ischemic stroke. This will be coupled with immunohistochemical, immunoblotting and biochemical analyses of EP receptors and MMP-3/-9. Specific Aim #2: To determine the therapeutic time window of protection and long-term effects of drugs modulating the COX-2/PGE2 pathway. Experiments in this aim test the hypothesis is that post- ischemic treatment with agents blocking ischemia-induced PGE2 formation/signaling provides neuroprotection without interfering in the late recovery phase. We will utilize an in vivo pharmacological approach together with innovative MRI techniques and a battery of tests to evaluate neurological function. The MRI approach will be coupled with immunohistochemical analyses to measure neurogenesis and angiogenesis. It is our expectation that this research will provide significant knowledge of the contribution of COX-2- derived PGE2 and its EP receptors to the neuroinflammatory process that follows ischemic stroke. We also expect to identify a clinically relevant therapeutic time window for the administration of drugs targeting COX- 2/PGE2. Such results would be expected to have an important positive impact, since they would identify novel and much-needed approaches to reduce the devastating consequences of stroke-induced BBB damage.

描述（由申请人提供）：神经炎症导致缺血性中风的进行性损伤。缺血性中风后 24-48 小时发生的血脑屏障 (BBB) 破坏是导致神经元死亡的病理机制。迫切需要确定限制中风后继发性损害的药理学策略。环氧合酶 (COX)-2/前列腺素 E2 (PGE2) 通路积极参与加剧初始缺血性脑损伤的炎症事件。我们的长期目标是了解如何操纵 COX-2/PGE2 通路来阻止缺血性中风后的进行性损伤级联反应。该项目的总体目标是确定 COX-2/PGE2 的增加如何介导缺血性中风中的 BBB 损伤和神经元死亡。我们的中心假设是，抑制 COX-2/PGE2 通路可通过减少 MMP-3/-9 的产生来防止 BBB 损伤和神经元死亡。拟议研究的基本原理是，了解 COX-2/PGE2 对中风的急性（有害）和晚期（可能有益）影响的机制应该确定新的靶标，以便使用阻断 COX-2/PGE2 的药物进行更具选择性和更有效的治疗干预。 2/PGE2 途径。具体目标#1：确定 COX-2 介导的 MMP-3/-9 表达/活性增加和缺血后 BBB 损伤的下游效应器。该目的的实验检验了以下假设：COX-2 衍生的 PGE2 通过激活局灶性缺血性脑损伤中的特定 EP 受体来诱导 MMP-3/-9 产生和 BBB 分解。我们将在完善的缺血性中风大鼠模型中利用体内药理学方法。这将与 EP 受体和 MMP-3/-9 的免疫组织化学、免疫印迹和生化分析相结合。具体目标#2：确定调节 COX-2/PGE2 途径的药物的保护治疗时间窗和长期效果。该目的的实验检验了以下假设：使用阻断缺血诱导的 PGE2 形成/信号转导的药物进行缺血后治疗可提供神经保护，而不会干扰后期恢复阶段。我们将利用体内药理学方法以及创新的 MRI 技术和一系列测试来评估神经功能。 MRI 方法将与免疫组织化学分析相结合，以测量神经发生和血管生成。我们期望这项研究能够提供关于 COX-2 衍生的 PGE2 及其 EP 受体对缺血性中风后神经炎症过程的贡献的重要知识。我们还期望确定针对 COX-2/PGE2 的药物给药的临床相关治疗时间窗。这些结果预计将产生重要的积极影响，因为它们将确定新颖且急需的方法来减少中风引起的血脑屏障损伤的破坏性后果。