Glial Interactions in Premyelinating Oligodendrocyte Destruction

髓鞘形成前少突胶质细胞破坏中的胶质细胞相互作用

• 批准号: 7504017
• 负责人: JIANRONG LI
• 金额: $ 31.83万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7504017
• 关键词: Astrocytes; Autopsy; Brain; Brain Hypoxia-Ischemia; Cause of Death; Cell Communication; Cell Death; Cells; Ceramide Signaling Pathway; Ceramides; Cerebral Palsy; Cerebrum; Cessation of life; Characteristics; Chronic; Clinical; Coculture Techniques; Condition; Conditioned Culture Media; Cultured Cells; Depth; 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; human TNF protein; injured; innovation; insight; intercellular communication; killings; novel strategies; oligodendrocyte precursor; prevent; second messenger; white matter; white matter injury

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(申请人提供)：脑室周围白质软化症(PVL)是脑性瘫痪的主要脑白质病变，也是早产幸存者慢性神经功能障碍的主要原因。与缺血/缺氧和母婴感染相关的炎症是PVL发病的主要决定因素，在脑白质具有特征性的星形胶质细胞增生和小胶质细胞激活。然而，在这些炎症条件下选择性损伤髓鞘前少突胶质细胞的机制尚不清楚。我们的长期目标是确定OL前损伤的分子基础，以便制定预防PVL的策略。最近，我们发现小胶质细胞在脂多糖(LPS)的激活下，通过产生过氧亚硝酸盐选择性地杀死前胶原细胞。有趣的是，虽然星形胶质细胞不是脂多糖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依赖过氧亚硝酸盐的机制切换到依赖于促炎细胞因子肿瘤坏死因子1(TNF1)的机制。在混合的神经胶质细胞培养中，暴露于TNF1会导致OL前死亡，但对纯化的前OL的影响很小。非损伤性水平的干扰素3大大增强了TNF1的毒性。这些观察结果强调了细胞间通讯在调节前OL死亡途径中的重要性。我们的初步结果还表明神经酰胺，一种神经鞘磷脂和脂质第二信使，是OL前损伤的常见介质，其在人PVL反应性星形胶质细胞中的表达显著增加。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作用于PVL中对前胶原细胞的损伤。我们将测试神经酰胺是炎症前OL死亡的关键因素，部分是通过与TNF1信号的相互作用。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介导的前OL死亡的机制；(3)探讨神经酰胺途径和TNF1介导的毒性之间协同作用的基础；(4)检查人PVL病变中神经酰胺异常上调、促炎细胞因子和OL前细胞死亡之间的空间相关性。我们将使用野生型和基因敲除小鼠的原代培养的各种组合来具体分析TNF1信号在介导OL前死亡中的作用。这个项目与以前的研究有很大的不同，因为我们直接专注于炎症损伤前OL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。对胶质细胞之间这种相互作用的基本见解可能会导致开发治疗PVL的新策略。 早产儿的白质损伤是新生儿重症监护幸存者终身神经缺陷的主要原因；炎症似乎在这种损伤中扮演了有害的角色。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加强，从而对脑白质造成损害。这些对新生儿脑白质损伤的细胞和分子机制的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的途径。