Cellular Basis of PVL in Autopsied Human Brain

尸检人脑中 PVL 的细胞基础

• 批准号: 7006500
• 负责人: HANNAH C KINNEY
• 金额: $ 34.74万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006500
• 关键词: astrocytes; brain injury; cell morphology; cellular pathology; cerebral cortex; cerebrovascular disorders; disease /disorder etiology; disease /disorder prevention /control; gene expression; glutathione transferase; gray matter; human fetus tissue; immune response; immunocytochemistry; in situ hybridization; inflammation; microglia; molecular pathology; myelin basic proteins; neurons; neuropathology; nitric oxide synthase; oligodendroglia; oxidative stress; postmortem; synaptogenesis; thalamus; tissue resource /registry; western blottings; white matter

The major causes of periventricular leukomalacia (PVL) in the premature infant are: 1) cerebral ischemia/reperfusion compounded by cerebral vascular immaturity and impaired autoregulation; and/or 2) maternofetal bacterial infection that triggers an inflammatory/cytokine response in the fetal brain. In the first grant cycle, our neuropathologic studies in human PVL demonstrated evidence for extensive free radical injury to premyelinating oligodendrocytes (pre-OLs) that is presumably triggered by cerebral ischemia and infection acting in concert. These studies also implicated critical roles for activated microglia and reactive astrocytes in contributing to or ameliorating this injury. Moreover, we found that PVL is associated with injury to gray matter sites critical to cognitive function, thus suggesting that this injury contributes to the long-term neurological handicaps in premature infants. The overall hypothesis of this Project is that nitrative and oxidative injury plays a major role in the pathogenesis of PVL and its associated injury in vulnerable gray matter sites. In six specific aims, we will examine in depth cellular features of nitrative and oxidative injury in PVL to vulnerable pre-OLs and now neurons, including subplate neurons. We also will determine factors in oligodendrocyte, astrocytic, microglial, and neuronal development that potentially place the immature white matter at risk. Under the auspices of our PVL Tissue Bank, we will accrue and analyze tissue samples with single- and double-labeled immunocytochemistry, in situ hybridization for mRNA, and western blot analysis for selected parameters related to free radical biology and injury, as well as the inflammatory response. The proposed specific aims, hypotheses, and approaches build upon the first cycle's findings in PVL, yet are novel and have the potential to lead to new insights into its pathogenesis. A full understanding of the cellular basis of PVL in the human brain is essential for establishing basic underlying mechanisms in directly relevant experimental models, in turn ultimately resulting in therapeutic interventions for testing in clinical trials.

早产儿脑室周围白质软化症（PVL）的主要病因是：1）脑 由脑血管不成熟和受损的自动调节复合的缺血/再灌注;和/或2）母胎细菌感染，其触发胎儿脑中的炎症/细胞因子应答。在第一个资助周期中，我们对人类PVL的神经病理学研究证明了广泛的自由基损伤前髓鞘少突胶质细胞（前OL）的证据，这可能是由脑缺血和感染共同触发的。这些研究还暗示了激活的小胶质细胞和反应性星形胶质细胞在促进或改善这种损伤中的关键作用。此外，我们发现PVL与灰质损伤有关 对认知功能至关重要的部位，因此表明这种损伤有助于早产儿的长期神经障碍。该项目的总体假设是，硝化和氧化损伤在PVL的发病机制及其在脆弱的灰质部位的相关损伤中起主要作用。在六个具体的目标，我们将深入研究的硝化和氧化损伤PVL脆弱的前OL和现在的神经元，包括subplate神经元的细胞特征。我们还将确定少突胶质细胞，星形胶质细胞， 小胶质细胞和神经元的发育，可能使未成熟的白色物质处于危险之中。在PVL组织库的支持下，我们将通过单标记和双标记免疫细胞化学、mRNA原位杂交和蛋白质印迹分析来收集和分析组织样本，以获得与自由基生物学和损伤以及炎症反应相关的选定参数。提出的具体目标，假设和方法建立在PVL的第一个周期的研究结果，但新颖的，并有可能导致其发病机制的新见解。充分理解PVL在人脑中的细胞基础对于在直接相关的实验模型中建立基本的潜在机制是必不可少的， 最终导致用于临床试验测试的治疗干预。