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：该程序的一个关键概念是脑室周围的白细胞藻类 （PVL）缺血/再灌注的结果，会触发自由基损伤 围产期白质中的少突胶质细胞的脆弱性，这是 产生少突胶质细胞的结果部分因细胞凋亡而死亡，因此导致 成熟的少突胶质细胞减少并损害髓鞘。总体 拟议的研究的假设是 将少突胶质细胞发展为脑白质中的氧化应激 PVL风险最大的时期（24-32周）至少在 部分，由于发育不足抗氧化剂酶的表达和/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 使用免疫细胞化学的人脑白质中的少突胶质细胞 具有标记物到特定阶段的少突胶质细胞的方法，检验假设 PVL风险最大的时期与 开发少突胶质细胞。我们还将确定发展概况 人类中铁代谢的选定抗氧化酶和标记 使用组织化学，免疫细胞化学和 免疫印迹。在这里，我们将测试抗氧化酶是 在最大的时期，在未成熟的白质中以低水平表达 PVL的风险，铁代谢标记的外观先前 抗氧化剂的表达，从而表示发育不匹配 在自由基的潜在来源和系统清除系统之间。在 PVL本身，我们将确定在 围绕PVL的白质，检验了有降低的假设 在发生少突胶质细胞的密度中，指示靶向死亡 和这些细胞的丢失。我们还将尝试确定是否发展 少突胶质细胞在PVL中凋亡。最后，我们将确定 选定的细胞因子在PVL中参与免疫细胞化学。提议 研究应为发展的角色提供重要的见解 与PVL中氧化应激有关的少突胶质细胞直接直接 人脑。