Ischemic Injury and Neuroprotection in the Immature Brain

未成熟大脑的缺血性损伤和神经保护

• 批准号: 7103130
• 负责人: ANNE M COMI
• 金额: $ 17.52万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7103130
• 关键词: anticonvulsants; apoptosis; atrophy; brain; brain injury; carotid artery; cell proliferation; cerebral ischemia /hypoxia; developmental neurobiology; dextromethorphan; disease /disorder model; drug screening /evaluation; epilepsy; gabapentin; infant animal; laboratory mouse; model design /development; necrosis; neuropathology; neuropharmacology; neuroprotectants; neuropsychological tests; phenytoin; stem cells; stroke; terminal nick end labeling

DESCRIPTION (provided by applicant): The career objective of this proposal is to permit the candidate, an academic child neurologist and recipient of a NINDS Neurological Scientist Academic Development Award (K12), to establish an independent research program in ischemic injury and neuroprotection in the immature brain. This Award would permit the candidate to characterize a highly promising animal model of stroke in the immature brain, develop expertise in endogenous stem cell proliferation after ischemia, and to gain facility in carrying out rigorous mouse trials of neuroprotection with anticonvulsants. Stroke in the term neonate or infant is an important cause of neurologic morbidity. Dr. Comi has developed a new immature mouse model of stroke utilizing unilateral carotid ligation alone to produce infarcts in immature mice. The vulnerability to injury varies with strain and age at surgery. We have shown in this model that dextromethorphan, an NMDA receptor antagonist with anticonvulsant actions, is neuroprotective. This research addresses the hypothesis that anticonvulsants will attenuate ischemic brain injury in the immature brain. The candidate's long term goal is rigorous pursuit of preclinical screening of neuroprotective strategies for ischemic injury in the developing brain and enhancement of the endogenous stem cell response after injury. The Specific Aims are to: 1) Characterize the evolution of brain injury and endogenous stem cell proliferation after unilateral carotid ligation. 2) Determine the extent of anticonvulsant neuroprotection. Stroke in the developing brain is an important cause of neurologic impairment that often persists into adulthood. An intervention providing even partial reduction of neurologic impairments would result in significant benefit both in terms of quality of life and decreased national healthcare costs. This work will provide important insights into the brain injury and regenerative response after stroke in this new immature mouse model and will test neuroprotective interventions with relevance to this population.

描述（由申请人提供）：该提案的职业目标是允许候选人，一位学术儿童神经学家和 NINDS 神经科学家学术发展奖（K12）的获得者，在缺血性损伤和神经保护领域建立一个独立的研究项目。不成熟的大脑。该奖项将使候选人能够在未成熟大脑中描述一种非常有前途的中风动物模型，发展缺血后内源性干细胞增殖的专业知识，并获得利用抗惊厥药物进行严格的小鼠神经保护试验的能力。新生儿或婴儿中风是神经系统发病的重要原因。 Comi 博士开发了一种新的未成熟小鼠中风模型，仅利用单侧颈动脉结扎在未成熟小鼠中产生梗塞。受伤的可能性因手术时的应变和年龄而异。我们在该模型中证明，右美沙芬（一种具有抗惊厥作用的 NMDA 受体拮抗剂）具有神经保护作用。这项研究提出了抗惊厥药可以减轻未成熟大脑的缺血性脑损伤的假设。该候选人的长期目标是严格追求针对发育中大脑缺血性损伤的神经保护策略的临床前筛选，并增强损伤后的内源干细胞反应。具体目标是： 1) 表征单侧颈动脉结扎后脑损伤和内源性干细胞增殖的演变。 2) 确定抗惊厥神经保护的程度。大脑发育中的中风是神经系统损伤的一个重要原因，这种损伤通常会持续到成年期。即使是部分减少神经损伤的干预措施也将在生活质量和降低国家医疗保健成本方面产生显着的效益。这项工作将为这种新的未成熟小鼠模型中的脑损伤和中风后的再生反应提供重要的见解，并将测试与该人群相关的神经保护干预措施。