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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.

我们的研究已经证实，有一个早期的再生反应是由