Cellular basis of PVL in autopsied brains

尸检大脑中PVL的细胞基础

• 批准号: 6565274
• 负责人: HANNAH C KINNEY
• 金额: $ 19.61万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6565274
• 关键词: antioxidants; apoptosis; cerebral degeneration; cerebral ischemia /hypoxia; cerebrovascular disorders; clinical research; cytokine; human tissue; immunocytochemistry; lipoxygenase; myelinopathy; oligodendroglia; oxidative stress; pathologic process; postmortem; premature infant human; tissue /cell culture

DESCRIPTION: A key concept of the program is that periventricular leukomalacia (PVL) results from ischemia/reperfusion that triggers free radical injury in vulnerable developing oligodendrocytes in perinatal white matter, and that, as a result developing oligodendrocytes die in part by apoptosis, thus resulting in decreased mature oligodendrocytes and impaired myelination. The overall hypothesis of the proposed study is that there is a specific vulnerability of developing oligodendrocytes to oxidative stress in the cerebral white matter in the period of greatest risk for PVL (24-32 weeks) which relates, at least in part, to a developmental lack of expression of antioxidant enzymes, and/or to the acquisition of iron necessary for oligodendrocyte differentiation. In baseline studies, we will determine the temporospatial maturation of oligodendrocytes in human cerebral white matter using immunocytochemical methods with markers to stage-specific oligodendrocytes, testing the hypothesis that the period of greatest risk for PVL coincides with a predominance of developing oligodendrocytes. We will also determine the developmental profile of selected antioxidant enzymes and markers of iron metabolism in human cerebral white matter using histochemistry, immunocytochemistry, and immunoblotting. Here we will test the hypotheses that antioxidant enzymes are expressed at low levels in immature white matter during the period of greatest risk for PVL, and that the appearance of markers of iron metabolism precedes the expression of antioxidant enzymes, thus denoting a developmental mismatch between potential sources of free radicals and the systems to clear them. In PVL itself, we will determine the densities of developing oligodendrocytes in white matter surrounding PVL, testing the hypothesis that there is a decrease in the density of developing oligodendrocytes, indicative of a targeted death and loss of these cells. We will also attempt to determine if developing oligodendrocytes undergo apoptosis in PVL. Finally, we will determine the involvement of selected cytokines in PVL with immunocytochemistry. The proposed studies should provide important insight into the roles of developing oligodendrocytes and factors related to oxidative stress in PVL directly within the human brain.

描述：该计划的一个关键概念是脑室周围白质软化症 (PVL) 是由缺血/再灌注引起的自由基损伤 围产期白质中脆弱的发育中的少突胶质细胞，并且， 结果，发育中的少突胶质细胞部分因细胞凋亡而死亡，从而导致 成熟少突胶质细胞减少和髓鞘形成受损。整体 拟议研究的假设是，存在特定的脆弱性 发育中的少突胶质细胞对脑白质氧化应激的影响 PVL 风险最大的时期（24-32 周）至少在以下方面相关： 部分原因是抗氧化酶表达的发育缺乏，和/或 获得少突胶质细胞分化所需的铁。在 基线研究，我们将确定时空成熟度 使用免疫细胞化学研究人脑白质中的少突胶质细胞 使用阶段特异性少突胶质细胞标记的方法，检验假设 PVL 风险最大的时期与 发育中的少突胶质细胞。我们还将确定发展概况 选定的抗氧化酶和人体铁代谢标记物 使用组织化学、免疫细胞化学和 免疫印迹。在这里我们将检验抗氧化酶的假设 在最大时期在未成熟白质中低水平表达 PVL 的风险，并且铁代谢标志物的出现先于 抗氧化酶的表达，从而表明发育不匹配 自由基的潜在来源和清除系统之间的关系。在 PVL 本身，我们将确定发育中少突胶质细胞的密度 PVL 周围的白质，检验 PVL 减少的假设 发育中的少突胶质细胞的密度，表明有针对性的死亡 以及这些细胞的损失。我们还将尝试确定是否正在开发 少突胶质细胞在 PVL 中发生凋亡。最后，我们将确定 通过免疫细胞化学研究PVL中选定的细胞因子的参与。拟议的 研究应该为发展中的作用提供重要的见解 少突胶质细胞和与PVL直接内部氧化应激相关的因素 人类的大脑。