Intranasal LIF to improve neurological recovery from perinatal hypoxia-ischema

鼻内 LIF 可改善围产期缺氧缺血的神经功能恢复

基本信息

批准号：
9980145
负责人：
STEVEN W LEVISON
金额：
$ 38.15万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9980145
关键词：
Action Potentials Animals Anxiety Apoptotic Astrocytes Axon Behavior Behavior Disorders Biological Assay Brain Hypoxia-Ischemia Brain Injuries Brain region Cell Death Cells Cerebral Palsy Cerebrum Cognition Disorders Cognitive Complement Corpus Callosum Data Development Diffusion Magnetic Resonance Imaging Discipline of obstetrics Electrophysiology (science)Emotional Epilepsy Flow Cytometry Genetic Goals Histologic Hypoxia Hypoxic-Ischemic Brain Injury Incidence Infant Inflammation Inflammatory Response Injury Intranasal Administration Knowledge LIF gene Lead Learning Life Memory Microglia Modeling Molecular Monitor Motor Mus Myelin Natural regeneration Nervous System Physiology Neuroglia Neurologic Neurologic Deficit Neuronal Injury Neurons Oligodendroglia Oxidative Stress Perinatal Perinatal Hypoxia Premature Birth Production Publishing Recovery Regenerative response Structure Testing Therapeutic Treatment Efficacy Wild Type Mouse antenatal astrogliosis axon injury axon regeneration behavioral impairment cell injury cell regeneration cytokine disability experimental study gliogenesis gray matter imaging study improved in vivo insight loss of function mortality motor disorder mouse model myelination neonatal care nerve stem cell neurogenesis neurological recovery neuron loss neuronal survival neurophysiology neuroprotection perinatal injury perinatal stroke preservation progenitor regenerative relating to nervous system repaired response stem stem cell niche stem cells subventricular zone therapeutic evaluation white matter

项目摘要

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.

我们的研究已经确定，有一个早期的再生反应在室室下区（SVZ）中的神经干细胞和祖细胞（NSP）对围产期低氧缺血（H-I）侮辱的反应，NSPS的扩张需要细胞因子白血病抑制剂（LIF）。我们收集了新数据揭示LIF的其他功能，因为LIF单位缺陷动物会承受更严重的伤害与野生型小鼠相比。补充功能研究的丧失，我们提供初步数据表明延迟鼻内LIF给药的数据降低了程度脑神经元丧失，增加SVZ的增殖并改善神经系统在近期缺氧 - 缺血的小鼠模型中的功能。因此，该建议是LIF是必不可少的神经保护和再生细胞因子并且非侵入性，鼻内施用LIF可以促进再生并减轻神经系统缺陷的长期负担。我们将通过使用前和近期小鼠进行实验来测试此前提围产期损伤的模型，以下3个特定目的：1）LIF单位缺陷型发育大脑后，小鼠将维持更大的神经元和神经胶质细胞损伤受伤伴随着恶性残疾的较差； 2）延迟鼻内LIF 给药将刺激干细胞和祖细胞的数量来修复灰色和白质损坏，3）轴突再生的程度和鼻内LIF给药可以改善功能。在我们的研究将阐明LIF发挥其有效性的机制神经保护和再生作用。由于可能发生许多围产期侮辱在产前时期，未被发现，从这些知识中获得的知识研究可能导致可以对婴儿进行治疗使受损的大脑能够正常从其内源干细胞发育，因此减少发病率和寿命长的认知，运动和情感障碍由于发育性脑损伤而发生。