Intranasal LIF to improve neurological recovery from perinatal hypoxia-ischema

我们的研究已经确定，有一个早期的再生反应启动， 脑室下区（SVZ）的神经干细胞和祖细胞（NSP） 对围产期缺氧缺血（H-I）损伤的反应，以及NSP的扩张 需要细胞因子白血病抑制因子（LIF）。我们收集了新的数据， 揭示了LIF的其他功能，因为LIF单倍缺陷动物遭受更严重的损伤 与野生型小鼠相比。补充这些功能丧失的研究，我们提供 初步数据显示，延迟鼻内LIF给药， 脑神经元丢失，增加SVZ的增殖并改善神经功能 在短期缺氧-缺血小鼠模型中的功能。因此， 这一观点认为LIF是一种重要的神经保护和再生细胞因子 并且LIF的非侵入性鼻内给药可以促进 再生和减少神经功能缺损的长期负担。我们将 通过使用早产和近足月小鼠进行实验来验证这一前提 围产期损伤模型，具有以下3个特定目的：1）LIF单倍缺陷 在大脑发育后，小鼠将承受更大的神经元和神经胶质细胞损伤， 损伤伴有更严重的神经功能障碍; 2）延迟鼻内LIF 给药将刺激干细胞和祖细胞的数量，以修复 受损的灰质和白色物质; 3）轴突再生的程度和 通过延迟鼻内给予LIF可以改善功能。过程中 我们的研究将阐明LIF发挥其强大作用的机制， 神经保护和再生作用。因为很可能许多围产期的伤害发生在 在产前期间和去未被发现，从这些知识获得 研究可能会导致治疗，可以给婴儿亚急性， 使受损的大脑能够从其内源性干细胞正常发育， 减少认知、运动和情感障碍的发生率和终生残疾， 是由于发育性脑损伤造成的

Our studies have established that there is an early regenerative response initiated by the neural stem cells and progenitors (NSPs) in the subventricular zone (SVZ) in response to a perinatal hypoxic-ischemic (H-I) insult and that the expansion of the NSPs requires the cytokine leukemia inhibitor factor (LIF). We have collected new data that reveals other functions of LIF as LIF haplodeficient animals sustain worse injury compared to wild type mice. Complementing those loss of function studies, we provide preliminary data to show that delayed intranasal LIF administration, reduces the extent of cerebral neuronal loss, increases proliferation in the SVZ and improves neurological function in a mouse model of near term hypoxia-ischemia. Therefore, the premise of this proposal is that LIF is an essential neuroprotective and regenerative cytokine and that the non-invasive, intranasal administration of LIF can promote regeneration and decrease the long-term burden of neurological deficits. We will test this premise by performing experiments using pre-term and near-term mouse models of perinatal injury with the following 3 specific aims: 1) that LIF haplodeficient mice will sustain greater neuronal and glial cell damage after a developmental brain injury accompanied by worse neurological disabilities; 2) that delayed intranasal LIF administration will stimulate the numbers of stem cells and progenitors to repair the damaged gray and white matter and 3) that the extent of axonal regeneration and function can be improved by delayed intranasal LIF administration. During the course of our studies we will elucidate the mechanisms through which LIF is exerting its potent neuroprotective and regenerative actions. As it is likely that many perinatal insults occur during the antenatal period and go undetected, the knowledge obtained from these studies could lead to therapeutics that could be administered to infants subacutely to enable the damaged brain to develop normally from its endogenous stem cells, thus decreasing the incidence and life long cognitive, motor and emotional handicaps that occur as a result of developmental brain damage.