MMP-12 and post-stroke brain damage

MMP-12 和中风后脑损伤

• 批准号: 9769893
• 负责人: Krishna Kumar Veeravalli
• 金额: $ 35.19万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769893
• 关键词: Acute; Alteplase; Animals; Apoptosis; Attenuated; Blood - brain barrier anatomy; Brain; Brain Infarction; Brain Injuries; Cell Death; Cerebral Ischemia; Cerebrum; Chronic Phase; Clinical; Clinical Research; Coagulation Process; Data; Demyelinations; Development; Disease; FDA approved; Female; Fibrinolytic Agents; Functional disorder; Future; Gelatinase A; Gelatinase B; Genes; Goals; Hypertension; Hypoxia; Inbred SHR Rats; Individual; Infarction; Inflammation; Inflammatory; Ischemia; Ischemic Stroke; Lead; MME gene; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Microglia; Middle Cerebral Artery Occlusion; Modeling; Molecular; Mus; Nerve; Nervous System Physiology; Neurological outcome; Outcome; Pathogenesis; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacotherapy; Plasmids; Plasminogen Activator; Procedures; Protein Isoforms; Rattus; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Rodent; Role; Source; Stroke; Surgical sutures; Techniques; Testing; Therapeutic; Thrombolytic Therapy; Time; Translating; Transmission Electron Microscopy; Work; aged; base; clinical development; experimental study; improved; inhibitor/antagonist; knock-down; macrophage; male; motor disorder; nanoparticle; neuroinflammation; neurological recovery; neuropathology; new therapeutic target; novel; patient subsets; post stroke; prevent; sex; small hairpin RNA; stroke outcome; stroke patient; stroke therapy; therapeutic target; thrombolysis; tissue repair; vasogenic edema; young adult

Project Summary/Abstract At present, tissue-type plasminogen activator (tPA) is the only FDA approved stroke therapy. tPA establishes reperfusion by thrombolysis of clots, but only a small subset of patients is eligible for tPA therapy. Moreover, the brain damage that occurs before and after tPA therapy is still an unmet clinical need. Identifying new therapeutic targets helps in developing novel and potent drugs to curtail post-stroke secondary brain damage. Our recent studies have shown that elevation of matrix metalloproteinase-12 (MMP-12) during reperfusion following transient focal ischemia in rodents contributes to BBB damage, apoptosis, and brain infarction. We currently hypothesize that the induction of MMP-12 contributes to post-stroke pathophysiology and compromises the neurologic outcome. Aim 1 is to characterize the role of MMP-12 in post-stroke brain damage and neurological recovery in both males and females as well as in a second species. Aim 2 is to unravel the source of MMP-12 and elucidate the molecular mechanisms underlying MMP-12-induced brain damage after stroke. Aim 3 is to investigate the efficacy of post-ischemic MMP-12 suppression in aged animals and animals with hypertension. We will use state of the art techniques including the shRNA-mediated knockdown of target genes by nanoparticle-mediated delivery of plasmids, suture model middle cerebral artery occlusion procedure, FACS analysis, and transmission electron microscopy to execute the proposed experiments. The long-term goal of this project is to develop post-stroke therapies that modulate MMP-12 to prevent secondary brain damage and promote neurological recovery.

项目总结/摘要 目前，组织型纤溶酶原激活剂（tPA）是FDA唯一批准的卒中治疗药物。tPA确立 通过血栓溶解再灌注，但只有一小部分患者适合tPA治疗。此外，委员会认为， 在tPA治疗之前和之后发生的脑损伤仍然是未满足的临床需求。确定新 治疗靶点有助于开发新型和有效的药物，以减少中风后继发性脑损伤。 我们最近的研究表明，再灌注过程中基质金属蛋白酶-12（MMP-12）的升高， 在啮齿类动物中，短暂局灶性缺血后导致BBB损伤、细胞凋亡和脑梗死。我们 目前假设MMP-12的诱导有助于中风后病理生理学， 会影响神经系统的预后目的1探讨MMP-12在脑卒中后脑组织中的作用 雄性和雌性以及第二个物种的损伤和神经恢复。目标二是 揭示MMP-12的来源，阐明MMP-12诱导脑损伤的分子机制 中风后的损伤目的3：探讨缺血后MMP-12抑制对老年人脑缺血再灌注损伤的影响。 动物和高血压动物。我们将使用最先进的技术，包括shRNA介导的 通过纳米颗粒介导的质粒递送敲低靶基因，缝合大脑中动脉模型 闭塞程序，FACS分析，和透射电子显微镜，以执行所提出的 实验该项目的长期目标是开发调节MMP-12的卒中后治疗， 防止继发性脑损伤，促进神经功能恢复。