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，一名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，建立一个独立的研究项目，研究未成熟大脑的缺血性损伤和神经保护。该奖项将允许候选人在未成熟大脑中描述一个非常有前途的中风动物模型，发展内源性干细胞缺血后增殖的专业知识，并获得进行抗惊厥药物神经保护的严格小鼠试验的能力。足月新生儿或婴儿中风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，利用单侧颈动脉结扎在未成熟小鼠中产生梗死。损伤的易损性随手术时的劳损和年龄而变化。我们已经在这个模型中表明右美沙芬，一种具有抗惊厥作用的NMDA受体拮抗剂，具有神经保护作用。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说。候选人的长期目标是严格追求在发育中的大脑缺血性损伤的神经保护策略的临床前筛选和损伤后内源性干细胞反应的增强。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)确定抗惊厥神经保护的程度。发育中的大脑中风是神经系统损伤的一个重要原因，通常会持续到成年。即使是部分减少神经损伤的干预措施，也会在生活质量和降低国家医疗保健费用方面产生重大效益。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.