tPA Neurotoxicity in Hypoxic-Ischemia Encephalopathy

tPA 在缺氧缺血性脑病中的神经毒性

• 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
• 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

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（由申请人提供）：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。虽然新生儿和成人对脑缺血缺氧有着共同的反应，但未成熟脑可能也有其独特的病理机制，在设计有效的治疗方法时值得特别考虑。我们的初步研究结果表明，缺血缺氧产生快速诱导的组织型和尿激酶型纤溶酶原激活剂（tPA和uPA），这与短暂血栓形成相一致。然而，tPA活性在脑灌注恢复后持续存在，并且位于缺血/缺氧激发的脑中的血管外。抗纤溶酶治疗减少缺血缺氧性脑损伤的程度，而外源性tPA的注射aversit. Based上这些结果，我们假设，新生儿有一个独特的反应，脑缺血缺氧的纤溶酶原激活剂诱导，这可能会限制血栓形成为基础的缺血性损伤，同时施加tPA和纤溶酶介导的神经毒性的风险增加。本项目将在两个具体目标中检验这一假设。目的一：利用转基因tPA/lacZ小鼠，鉴定新生儿脑缺血缺氧时tPA产生细胞。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溶中的作用。在目的2中，我们将比较侧脑室注射α 2-抗纤溶酶（一种纤溶酶抑制剂）、派-1（抑制tPA和uPA）和neuroserpin（tPA特异性但覆盖tPA的纤溶酶非依赖性毒性）对新生儿缺血缺氧性脑损伤的保护作用。将在多个时间点使用不同方法检查这些治疗的疗效。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。新生儿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，但其潜在机制尚不清楚。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）的急性和持续活性，导致蛋白水解型脑损伤。将在tPA无效动物中以及通过在新生儿脑缺血-缺氧后给予抗tPA/纤溶酶试剂来检验该假设。