CEREBRAL MALARIA-INDUCED APOPTOSIS AND BRAIN PATHOLOGY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 疟疾(恶性疟原虫)感染全球2亿至3亿人，每年导致200万人死亡(主要是儿童)。15%的死亡病例是由脑型疟疾和其他严重形式的疟疾引起的。不管推荐的治疗方法如何，很大一部分CM患者都会死亡。相当数量的幸存者会出现神经系统并发症和认知问题。CM引起的脑损伤和预后不良的确切机制尚不清楚。假设疟原虫凋亡因子S(PAF)诱导神经元和微血管内皮细胞凋亡，选择性阻断PAF介导的凋亡将否定或显着减少细胞凋亡和CM诱导的病理改变。 我们的目的是利用人脑内皮细胞(HBVEC)、神经胶质细胞和神经细胞系，以及我们建立的啮齿动物CM模型，分别鉴定和表征PAF在CM诱导的脑病理中的作用。我们利用基因组学、蛋白质组学、免疫学方法、成像技术、超微结构分析和靶向基因失活(RNA干扰，RNAi)来追求这些目标。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Malaria (P. falciparum) infects 200 to 300 million people globally and kills 2 million (mostly children) every year. 15% of fatal cases are due to cerebral malaria (CM) and other severe forms of malaria. A significant segment of CM patients die regardless of recommended treatment. A significant number of survivors develop neurological complications and cognition problems. The precise mechanisms responsible for CM induced brain damage and poor prognosis is unclear. The hypothesis is that Plasmodium apoptotic factor(s) (PAF) induce neuronal and microvascular endothelial cell apoptosis and that selectively blocking PAF mediated apoptosis will negate or significantly reduce apoptosis and CM-induced pathology. Our objective was to identify and characterize the role of PAF in CM-induced brain pathology using human brain endothelial (HBVEC), glial, and neuronal cell lines, as well as our established rodent CM model respectively. We utilized genomics, proteomics, immunological methods, imaging techniques, ultrastructural analysis, and targeted gene inactivation (RNA interference, RNAi) to pursue these goals.