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）：神经炎症会导致缺血性中风的逐渐损害。缺血性中风后24-48 h发生的血脑屏障（BBB）的破坏是一种病理机制，有助于神经元死亡。迫切需要确定限制中风后次要损害的药理策略。环氧合酶（COX）-2/Prostaglandin E2（PGE2）途径积极参与加剧初始缺血性脑损伤的炎性事件。我们的长期目标是了解如何操纵COX-2/PGE2途径以阻止缺血性中风后进行性损伤级联。该项目的总体目标是确定增加的COX-2/PGE2如何介导缺血性中风中BBB损伤和神经元死亡。我们的中心假设是抑制COX-2/PGE2途径可通过减少MMP-3/-9产生来防止BBB损伤和神经元死亡。拟议的研究的基本原理是，了解COX-2/PGE2在中风中涉及的急性（有害）和晚期（可能是有益的）作用的机制，应确定新的靶标，以通过药物阻止COX-2/PGE2途径进行更有选择性和有效的治疗干预措施。具体目标＃1：确定COX-2介导的MMP-3/-9表达/活性增加的下游效应因素以及缺血后对BBB的损害。该目标中的实验检验了以下假设：COX-2衍生的PGE2通过激活特定EP受体在局灶性缺血性脑损伤中诱导MMP-3/-9的产生和BBB分解。我们将在良好的缺血性中风大鼠模型中利用体内药理方法。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。特定目的＃2：确定保护COX-2/PGE2途径的药物的保护时间窗口和长期影响。在此目标测试中的实验假设是，用阻断缺血诱导的PGE2形成/信号传导的药物治疗后的缺血后治疗可提供神经保护，而无需干扰晚期恢复阶段。我们将利用一种体内药理方法以及创新的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。我们期望这项研究将对COX-2衍生的PGE2及其EP受体的贡献提供重要的了解，而EP受体对缺血性中风后的神经炎症过程。我们还希望确定针对Cox 2/pge2的药物的临床相关治疗时间窗口。预计此类结果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BBB损害的破坏性后果。