tPA Neurotoxicity in Hypoxic-Ischemia Encephalopathy

tPA 在缺氧缺血性脑病中的神经毒性

基本信息

批准号：
7476040
负责人：
Chia-Yi Kuan
金额：
$ 19.69万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7476040
关键词：
Acute Adult Age Animals Antiplasmin Asphyxia Astrocytes Attenuated Base of the Brain Behavior Behavioral Assay Biological Preservation Birth Blood - brain barrier anatomy Blood Platelets Blood Vessels Brain Brain Hypoxia-Ischemia Brain Injuries Cells Cerebral Ischemia-Hypoxia Cerebral Palsy Cerebrovascular Circulation Cerebrum Deposition Disease Encephalopathies Endopeptidases Endothelium Engineering Epilepsy Fibrin Fibrinolysis Histocompatibility Testing Hypoxia Incidence Injection of therapeutic agent Injury Ischemia Ischemic-Hypoxic Encephalopathy Knockout Mice Label LacZ Genes Learning Learning Disabilities Measures Mediating Mental Retardation Methods Microglia Modeling Morbidity - disease rate Mus Mutant Strains Mice Neonatal Nervous System Physiology Newborn Infant Pathologic Pathologic Processes Peptide Hydrolases Perfusion Perinatal Brain Injury Pharmaceutical Preparations Plasmin Plasmin Inhibitor Plasminogen Plasminogen Activator Plasminogen Activator Inhibitor 1 Process Production Proteolysis Public Health Purpose Rattus Recovery Research Proposals Risk Rodent Rodent Model Role Staining method Stains Testing Therapeutic Thrombosis Thrombus Time Toxic effect Transcript Transgenic Organisms Treatment Efficacy Urokinase Ventricular base behavior test brain tissue cell type cytokine day design mortality neonatal hypoxic-ischemic brain injury neonate neuron apoptosis neuroserpin neurotoxicity novel novel therapeutics promoter pup response success therapeutic target treatment effect urinary white matter injury young adult

项目摘要

DESCRIPTION (provided by applicant): Hypoxic-ischemic encephalopathy caused by birth asphyxia is a leading cause of brain injury in newborns. Although neonates and adults have common responses to cerebral ischemia-hypoxia, the immature brains may also have unique pathologic mechanism that deserves special consideration for designing effective therapies. Our preliminary results indicated that ischemia-hypoxia produces a rapid induction of tissue-type and urokinase-type plasminogen activators (tPA and uPA) that coincides with transient thrombosis. However, the tPA activity persists after recovery of cerebral perfusion, and is located outside blood vessels in the ischemia/hypoxia-challenged brains. Anti-plasmin treatment reduces the extent of ischemic- hypoxic brain injury, whereas the injection of exogenous tPA worsens it. Based on these results, we hypothesize that neonates have a unique response to cerebral ischemia-hypoxia in plasminogen activator induction, which may limit thrombosis-based ischemic injury, while imposing increased risk of tPA and plasmin-mediated neurotoxicity. The present project will test this hypothesis in two specific aims. In Aim 1, we will use transgenic tPA/lacZ mice to identify the tPA-producing cells in neonatal cerebral ischemia-hypoxia. We will also use engineered mutant mice to test the roles of tPA and uPA in spontaneous fibrinolysis in this setting. In Aim 2, we will compare the effects of cerebroventricular injection of a2-antiplasmin (a Plasmin inhibitor), PAI-1 (inhibiting both tPA and uPA), and neuroserpin (tPA-specific but covering plasmin-independent toxicity of tPA) in protecting against ischemic-hypoxic brain injury in the neonates. The efficacy of these treatments will be examined at multiple time-points using different methods. In summary, the present project will test a novel mechanism of neonatal hypoxic- ischemic encephalopathy using a rodent model. Success of this project will suggest new therapy of this devastating disease in newborns. PUBLIC HEALTH RELEVANCE Hypoxic-ischemic encephalopathy caused by birth asphyxia is the single most important cause of brain injury in newborns, but its underlying mechanisms remain unclear. The central hypothesis of this proposal states that ischemia-hypoxia in the newborn brain induces acute and persistent activity of the endogenous plasminogen activators, including tPA and uPA, leading to proteolysis-type brain injury. This hypothesis will be tested in tPA-null animals and by administration of anti-tPA/Plasmin agents after neonatal cerebral ischemia-hypoxia.

描述（申请人提供）：出生窒息引起的缺氧缺血性脑病是新生儿脑损伤的主要原因。尽管新生儿和成人对脑缺血缺氧有共同的反应，但未成熟的大脑也可能具有独特的病理机制，在设计有效的治疗方法时值得特别考虑。我们的初步结果表明，缺血缺氧会快速诱导组织型和尿激酶型纤溶酶原激活剂（tPA 和 uPA），这与短暂性血栓形成同时发生。然而，tPA 活性在脑灌注恢复后仍然存在，并且位于缺血/缺氧大脑的血管外。抗纤溶酶治疗可减轻缺血缺氧性脑损伤的程度，而注射外源性 tPA 则会使其恶化。基于这些结果，我们假设新生儿在纤溶酶原激活剂诱导中对脑缺血缺氧有独特的反应，这可能会限制基于血栓形成的缺血性损伤，同时增加 tPA 和纤溶酶介导的神经毒性的风险。目前的项目将在两个具体目标上测试这一假设。在目标 1 中，我们将使用转基因 tPA/lacZ 小鼠来鉴定新生儿脑缺血缺氧中产生 tPA 的细胞。我们还将使用工程突变小鼠来测试 tPA 和 uPA 在这种情况下自发纤维蛋白溶解中的作用。在目标 2 中，我们将比较脑室注射 a2-抗纤溶酶（纤溶酶抑制剂）、PAI-1（同时抑制 tPA 和 uPA）和神经丝氨酸蛋白酶抑制剂（tPA 特异性但涵盖 tPA 的纤溶酶非依赖性毒性）在保护对抗新生儿缺血缺氧性脑损伤。这些治疗的疗效将在多个时间点使用不同的方法进行检查。总之，本项目将使用啮齿动物模型测试新生儿缺氧缺血性脑病的新机制。该项目的成功将为新生儿这种毁灭性疾病提供新的治疗方法。公共卫生相关性出生窒息引起的缺氧缺血性脑病是新生儿脑损伤的最重要原因，但其潜在机制仍不清楚。该提案的中心假设指出，新生儿大脑缺血缺氧会诱导内源性纤溶酶原激活剂（包括 tPA 和 uPA）急性且持续的活动，导致蛋白水解型脑损伤。该假设将在 tPA 缺失的动物中进行测试，并通过在新生儿脑缺血缺氧后施用抗 tPA/纤溶酶制剂来进行测试。