Ischemic Injury and Neuroprotection in the Immature Brain

描述(由申请人提供)：这项提议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，在未成熟的大脑中建立一个关于缺血性损伤和神经保护的独立研究计划。这一奖项将允许候选人在未成熟的大脑中描述一种非常有希望的中风动物模型，发展缺血后内源性干细胞增殖方面的专业知识，并在使用抗惊厥药物进行严格的小鼠神经保护试验方面获得便利。新生儿或婴儿时期的中风是导致神经系统疾病的重要原因。科米博士开发了一种新的未成熟小鼠中风模型，仅用单侧颈动脉结扎就能在未成熟小鼠身上造成脑梗塞。手术时易受损伤的程度因劳损和年龄而异。我们已经在这个模型中证明了右美沙芬，一种具有抗惊厥作用的NMDA受体拮抗剂，具有神经保护作用。这项研究提出了一种假设，即抗惊厥药物将减轻未成熟大脑中的缺血性脑损伤。候选人的长期目标是严格追求临床前筛选发育中脑缺血损伤的神经保护策略，并增强损伤后的内源性干细胞反应。1)研究单侧颈动脉结扎后脑损伤的演变及内源性干细胞增殖情况。2)确定抗惊厥药物的神经保护程度。大脑发育中的中风是神经损伤的一个重要原因，这种损伤通常会持续到成年。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成本方面带来显著的好处。这项工作将为这一新的未成熟小鼠模型中中风后的脑损伤和再生反应提供重要的见解，并将测试与这一群体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.