Reversing inflammatory macrophage activation as treatment for neonatal intraventricular hemorrhage and hydrocephalus

逆转炎症巨噬细胞活化治疗新生儿脑室内出血和脑积水

基本信息

批准号：
9977341
负责人：
BRANDON A MILLER
金额：
$ 18.54万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9977341
关键词：
Activation Analysis Adult Affect Animals Anti-Inflammatory Agents Antibiotics Antibodies Azithromycin Birth Bone Marrow Brain Brain Injuries Bromodeoxyuridine Cell Communication Cell Death Cell Maturation Cell Survival Cell division Cells Central Nervous System Diseases Cerebral Ventricles Cerebrum Child Childhood Injury Clinical Clinical Research Clinical Trials Cognitive deficits Data Development Dichloromethylene Diphosphonate Disease Failure Goals Hematogenous Hemoglobin Hemorrhage Hydrocephalus Immunochemistry Immunohistochemistry In Vitro Infiltration Inflammation Inflammatory Injections Injury Interruption Intraventricular Liquid substance Macrophage Activation Maps Measures Mediating Medical Messenger RNA Microglia Modeling Myelin Myelin Basic Proteins Myelogenous NF-kappa B Neonatal Neonatal Brain Injury Nervous System Physiology Neurological outcome Nucleic Acids Oligodendroglia Outcome Oxidative Stress Oxides Peripheral Pharmaceutical Preparations Pharmacology Phenotype Premature Birth Premature Infant Process Production Property Rattus Recovery Role Site Spinal cord injury Stimulus TNF gene Testing Therapeutic Time Tissues Training Ventricular Western Blotting Work blood product brain cell cell type central nervous system injury chemokine cytokine disability excitotoxicity experimental study functional improvement improved improved outcome in vitro Model in vivo intraventricular hemorrhage lateral ventricle lung injury mRNA Expression macrophage monocyte myelination neonatal brain neonate nervous system disorder neurobehavioral neuroinflammation oligodendrocyte progenitor pre-clinical preservation protein expression recruit repaired response self renewing cell stem cells white matter white matter injury

Activation Analysis Adult Affect Animals Anti-Inflammatory Agents Antibiotics Antibodies Azithromycin Birth Bone Marrow Brain Brain Injuries Bromodeoxyuridine Cell Communication Cell Death Cell Maturation Cell Survival Cell division Cells Central Nervous System Diseases Cerebral Ventricles Cerebrum Child Childhood Injury Clinical Clinical Research Clinical Trials Cognitive deficits Data Development Dichloromethylene Diphosphonate Disease Failure Goals Hematogenous Hemoglobin Hemorrhage Hydrocephalus Immunochemistry Immunohistochemistry In Vitro Infiltration Inflammation Inflammatory Injections Injury Interruption Intraventricular Liquid substance Macrophage Activation Maps Measures Mediating Medical Messenger RNA Microglia Modeling Myelin Myelin Basic Proteins Myelogenous NF-kappa B Neonatal Neonatal Brain Injury Nervous System Physiology Neurological outcome Nucleic Acids Oligodendroglia Outcome Oxidative Stress Oxides Peripheral Pharmaceutical Preparations Pharmacology Phenotype Premature Birth Premature Infant Process Production Property Rattus Recovery Role Site Spinal cord injury Stimulus TNF gene Testing Therapeutic Time Tissues Training Ventricular Western Blotting Work blood product brain cell cell type central nervous system injury chemokine cytokine disability excitotoxicity experimental study functional improvement improved improved outcome in vitro Model in vivo intraventricular hemorrhage lateral ventricle lung injury mRNA Expression macrophage monocyte myelination neonatal brain neonate nervous system disorder neurobehavioral neuroinflammation oligodendrocyte progenitor pre-clinical preservation protein expression recruit repaired response self renewing cell stem cells white matter white matter injury

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项目摘要

Neonatal Intraventricular hemorrhage (IVH) originates from the underdeveloped germinal matrix, a site of cell rapid cell division adjacent to the lateral ventricles of the brain. IVH leads to post-hemorrhagic hydrocephalus (PHH). Within the same time frame that neonatal IVH occurs, the neonatal brain is also rapidly producing the cells needed for myelination. Oligodendrocytes, the myelin-forming cells of the brain, are derived from oligodendrocyte progenitor cells (OPCs). OPCs are fragile cells - exquisitely sensitive to many factors that are present across multiple neurological diseases such as excitotoxicity, inflammatory cytokines, and oxidative stress. Across a wide spectrum of neurological diseases, neuroinflammation causes OPC loss and failure of myelination. Infiltrating brain macrophages are implicated in many forms of neonatal brain injury. Macrophages are activated by many different stimuli in CNS injury and disease, including blood products released into the ventricular space. Understanding the role of macrophages after IVH is critical to improving outcomes, as macrophage activation mediates white matter injury in other forms of neonatal brain injury. Azithromycin is a commonly prescribed antibiotic that is safe in neonates. Besides its antibiotic properties, azithromycin is also anti-inflammatory and shifts macrophage activation into an anti-inflammatory phenotype that actually promotes tissue recovery rather than injury. Azithromycin has been used in a variety of anti-inflammatory applications including preclinical work in spinal cord injury where it improves tissue sparing and neurological function. Importantly, azithromycin has already undergone rigorous clinical trials in neonates for inflammation-induced lung injury. This study will pharmacologically block infiltrating macrophages in IVH/PHH and test azithromycin’s ability to protect OPCs from macrophage-induced injury in a rat model of neonatal IVH. I will use a combination of in vivo and in vitro experiments to examine macrophage activation, OPC death and myelination with and without azithromycin treatment. My in vivo work will allow us to use neurobehavioral outcomes to assess the efficacy of azithromycin while my in vitro model will allow for in-depth mechanistic studies of macrophage-OPC interaction. This project will support Dr. Miller’s training in studies of neuroinflammation and neurotherapeutics. If successful, this project will pave the way for clinical studies of azithromycin for improving neurological outcome after neonatal IVH.

新生儿脑室出血（IVH）起源于欠发育的生发基质细胞快速细胞分裂毗邻大脑的侧心。 IVH导致后诊断脑积水（PHH）。在新生儿IVH发生的同一时间范围内，新生儿大脑也很快产生髓鞘形成所需的细胞。少突胶质细胞，大脑的髓磷脂形成细胞，得出来自少突胶质细胞祖细胞（OPC）。 OPC是脆弱的细胞 - 对许多因素敏感存在于多种神经系统疾病中，例如兴奋性毒性，炎性细胞因子和氧化性压力。在广泛的神经疾病中，神经炎症会导致OPC丧失和失败髓鞘。浸润的脑巨噬细胞以多种形式的新生儿脑损伤实施。巨噬细胞在中枢神经系统损伤和疾病中，许多不同的刺激激活心室空间。了解IVH后巨噬细胞的作用对于改善结果至关重要，因为巨噬细胞激活介导其他形式的新生儿脑损伤中的白质损伤。阿奇霉素是一种普遍处方的抗生素，在新生儿中是安全的。除了其抗生素特性，阿奇霉素也具有抗炎作用，并将巨噬细胞激活转移到抗炎实际促进组织恢复而不是损伤的表型。阿奇霉素已用于多种抗炎应用，包括脊髓损伤中的临床前工作，改善了组织的保留和神经功能。重要的是，阿奇霉素已经在新生儿进行了严格的临床试验用于炎症引起的肺损伤。这项研究将在物理上阻止渗透巨噬细胞 IVH/PHH和测试阿奇霉素在大鼠模型中保护OPC免受巨噬细胞诱导的损伤的能力新生儿IVH。我将使用体内和体外实验的组合来检查巨噬细胞的激活， OPC死亡和髓鞘形成和没有阿奇霉素治疗。我的体内工作将使我们能够使用神经行为结局，以评估阿奇霉素的效率，而我的体外模型将允许深入巨噬细胞 - OPC相互作用的机械研究。该项目将支持米勒博士在研究方面的培训神经炎症和神经疗法。如果成功，该项目将为临床研究铺平道路阿奇霉素用于改善新生儿IVH后神经系统结局。