Ischemic Injury and Neuroprotection in the Immature Brain

描述（由申请人提供）：本提案的职业目标是允许候选人，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，建立未成熟大脑缺血性损伤和神经保护的独立研究计划。该奖项将允许候选人描述一个非常有前途的未成熟大脑中风动物模型，发展缺血后内源性干细胞增殖的专业知识，并获得进行抗惊厥药物神经保护的严格小鼠试验的便利。新生儿或婴儿期卒中是神经系统疾病的重要原因。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死。受伤的脆弱性随着手术时的应变和年龄而变化。我们已经在该模型中表明，具有抗惊厥作用的NMDA受体拮抗剂二甲双胍具有神经保护作用。本研究提出了抗惊厥药可减轻未成熟脑缺血性脑损伤的假设。候选人的长期目标是严格追求临床前筛选发育中大脑缺血性损伤的神经保护策略，并增强损伤后的内源性干细胞反应。具体目的是：1）描述单侧颈动脉结扎后脑损伤和内源性干细胞增殖的演变。2)确定抗惊厥药神经保护的程度。发育中的大脑中风是神经功能障碍的重要原因，通常持续到成年期。即使是部分减少神经功能障碍的干预措施，也会在生活质量和降低国家医疗保健成本方面带来显著益处。这项工作将为这种新的未成熟小鼠模型中风后的脑损伤和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。

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.