Glial Interactions in Premyelinating Oligodendrocyte Destruction

髓鞘形成前少突胶质细胞破坏中神经胶质细胞的相互作用

基本信息

批准号：
7876812
负责人：
JIANRONG LI
金额：
$ 31.51万
依托单位：
TEXAS A&M UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7876812
关键词：
Astrocytes Autopsy Brain Brain Hypoxia-Ischemia Cause of Death Cell Communication Cell Culture Techniques Cell Death Cells Ceramide Signaling Pathway Ceramides Cerebral Palsy Cerebrum Cessation of life Characteristics Chronic Clinical Coculture Techniques Conditioned Culture Media Development Diffuse Disease Exposure to Genes Goals Human In Vitro Inflammation Inflammatory Injury Interferons Knockout Mice Knowledge Laboratories Lead Lesion Life Lipids Lipopolysaccharides Mediating Mediator of activation protein Microglia Modeling Molecular Mus Neonatal Neonatal Brain Injury Neonatal Intensive Care Neuroglia Neurologic Nitric Oxide Oligodendroglia Pathogenesis Pathway interactions Periventricular Leukomalacia Peroxonitrite Play Premature Birth Premature Infant Prevention Primary Cell Cultures Production Reaction Role Second Messenger Systems Signal Pathway Signal Transduction Sphingomyelins Superoxides Survivors Testing Toxic effect Tumor Necrosis Factor-alpha Tumor Necrosis Factors Up-Regulation astrogliosis base cell type cytokine disability fetal infection injured innovation insight intercellular communication killings novel strategies oligodendrocyte precursor prevent second messenger white matter white matter injury

项目摘要

DESCRIPTION (provided by applicant): Periventricular leukomalacia (PVL) is the principal white matter lesion underlying cerebral palsy and a leading cause of chronic neurological deficits in survivors of premature birth. Inflammation associated with ischemia/hypoxia and maternal/fetal infection is a major determinant of the pathogenesis of PVL, with characteristic astrogliosis and microglial activation in the cerebral white matter. However, the mechanism of selective injury to premyelinating oligodendrocytes (pre-OLs) under these inflammatory conditions is poorly understood. Our long-term goal is to determine the molecular basis of pre-OL injury in order to develop strategies to prevent PVL. Recently, we showed that microglia, activated by lipopolysaccaride (LPS), selectively kill pre-OLs by producing peroxynitrite. Interestingly, although astrocytes are not required for LPS-induced toxicity, their presence switches the activated microglial toxicity from a peroxynitrite- dependent mechanism to a mechanism dependent upon the proinflammatory cytokine, tumor necrosis factor 1 (TNF1). Exposure to TNF1 results in pre-OL death in mixed glial cultures but had only minimal effect to purified pre-OLs. Non-injurious levels of interferon 3 greatly potentiate the TNF1 toxicity. These observations underscore the importance of cell-to-cell communications in regulating pre-OL death pathways. Our preliminary results also suggest that ceramide, a sphingomyelin lipid and a lipid second messenger, acts as a common mediator for pre-OL injury, and that its expression is markedly increased in reactive astrocytes in human PVL. Our overall hypothesis is that activated microglia and astrocytes act corporately in mediating injury to pre-OLs in PVL. We will test the idea that ceramide is a key factor in inflammatory pre-OL death, in part via interactions with TNF1 signaling. Our Specific Aims are to: (1) determine the inhibitory effect of astrocytes on peroxynitrite-induced toxicity to pre-OLs; (2) identify the mechanisms underlying TNF1- mediated pre-OL death; (3) investigate the basis of synergy between the ceramide pathway and TNF1- mediated toxicity; and (4) examine spatial correlations among aberrant upregulation of ceramide, proinflammatory cytokines, and pre-OL cell death in human PVL lesions. We will use various combinations of primary cultures from wildtype and knockout mice to specifically dissect TNF1 signaling in mediating pre-OL death. This project is a significant departure from previous studies in that we focus directly on the molecular and intercellular mechanisms of inflammatory injury to pre-OLs and integrate cell culture studies with human PVL studies. Fundamental insights into such interactions among glial cells could lead to development of novel strategies for the treatment of PVL.PROJECT NARRATIVE White matter injury in preterm infants is a major cause of life-long neurological deficits in survivors of neonatal intensive care; and inflammation appears to play a deleterious role in the injury. Through this proposed study, we hope to reveal how various cells interact and intensify with each other and cause damage to the white matter. Such fundamental insights into the cellular and molecular mechanisms of neonatal white matter injury will provide new avenues for developing novel strategies for the prevention and treatment of this devastating disorder.

描述（由申请人提供）：脑室周围白质软化症（PVL）是脑瘫的主要白质病变，也是早产幸存者慢性神经功能缺损的主要原因。与缺血/缺氧和母体/胎儿感染相关的炎症是PVL发病机制的主要决定因素，具有大脑白质中特征性的星形胶质细胞增生和小胶质细胞激活。然而，人们对这些炎症条件下髓鞘形成前少突胶质细胞（pre-OL）选择性损伤的机制知之甚少。我们的长期目标是确定 OL 损伤前的分子基础，以便制定预防 PVL 的策略。最近，我们发现，脂多糖（LPS）激活的小胶质细胞通过产生过氧亚硝酸盐选择性地杀死前OL。有趣的是，虽然星形胶质细胞不是 LPS 诱导的毒性所必需的，但它们的存在将激活的小胶质细胞毒性从过氧亚硝酸盐依赖性机制转变为依赖于促炎细胞因子肿瘤坏死因子 1 (TNF1) 的机制。暴露于 TNF1 会导致混合神经胶质培养物中前 OL 死亡，但对纯化的前 OL 影响极小。非有害水平的干扰素 3 会大大增强 TNF1 的毒性。这些观察结果强调了细胞间通讯在调节 OL 前死亡途径中的重要性。我们的初步结果还表明，神经酰胺（一种鞘磷脂脂质和脂质第二信使）充当 OL 前损伤的常见介质，并且其表达在人 PVL 的反应性星形胶质细胞中显着增加。我们的总体假设是，激活的小胶质细胞和星形胶质细胞共同介导 PVL 中前 OL 的损伤。我们将测试神经酰胺是炎症前 OL 死亡的关键因素这一观点，部分是通过与 TNF1 信号传导的相互作用实现的。我们的具体目标是： (1) 确定星形胶质细胞对过氧亚硝酸盐诱导的前 OL 毒性的抑制作用； (2)确定TNF1介导的OL前死亡的潜在机制； (3)研究神经酰胺途径与TNF1介导的毒性之间协同作用的基础； (4) 检查人类 PVL 病变中神经酰胺、促炎细胞因子和前 OL 细胞死亡的异常上调之间的空间相关性。我们将使用来自野生型和基因敲除小鼠的原代培养物的各种组合来专门剖析 TNF1 信号在介导 OL 前死亡中的作用。该项目与之前的研究有很大不同，我们直接关注前 OL 炎症损伤的分子和细胞间机制，并将细胞培养研究与人类 PVL 研究相结合。对神经胶质细胞之间这种相互作用的基本了解可能会导致治疗 PVL 的新策略的开发。项目叙述早产儿脑白质损伤是新生儿重症监护幸存者终生神经功能缺损的主要原因；炎症似乎在损伤中发挥着有害作用。通过这项拟议的研究，我们希望揭示各种细胞如何相互作用和相互作用以及如何对白质造成损害。对新生儿白质损伤的细胞和分子机制的这种基本见解将为开发预防和治疗这种破坏性疾病的新策略提供新途径。