Identifying adjunctive therapy in the experimental model of malaria to improve cerebral malaria outcomes

确定疟疾实验模型中的辅助治疗以改善脑型疟疾的结果

基本信息

批准号：
10238203
负责人：
Johanna Patricia Daily
金额：
$ 25.2万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-11 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238203
关键词：
Animal Model Anti-Inflammatory Agents Antimalarials Antioxidants Biological Assay Blood - brain barrier anatomy Blood Vessels Brain Brain Edema Brain Pathology Cause of Death Cerebral Malaria Cerebrovascular Circulation Cessation of life Clinical Clinical Data Clinical Management Clinical Research Clinical Trials Coculture Techniques Coma Complication Confocal Microscopy Data Death Rate Development Disease Edema Erythroid Experimental Models FDA approved Foundations Fright Fumarates Future Goals Health Hemorrhage Histology Histopathology Human Imaging Techniques Imaging technology Immunofluorescence Microscopy Individual Infection Inflammation Inflammatory Magnetic Resonance Imaging Malaria Measures Modeling Morbidity - disease rate Multiple Sclerosis Neuraxis Neurologic Neurologic Deficit Neurological status Nuclear Outcome Oxidative Stress Parasites Pathogenesis Pathology Pathway interactions Patients Permeability Pharmaceutical Preparations Plasmodium falciparum Pre-Clinical Model Protective Agents Proteins Public Health Reporting Research Site Spleen Stroke Techniques Testing Therapeutic Agents Therapeutic Effect Tight Junctions Up-Regulation blood-brain barrier permeabilization brain endothelial cell cytotoxic disability improved improved outcome in vitro Model insight mortality mouse model neuroimaging neuroinflammation pre-clinical protective effect survival outcome systemic inflammatory response therapeutic evaluation

Animal Model Anti-Inflammatory Agents Antimalarials Antioxidants Biological Assay Blood - brain barrier anatomy Blood Vessels Brain Brain Edema Brain Pathology Cause of Death Cerebral Malaria Cerebrovascular Circulation Cessation of life Clinical Clinical Data Clinical Management Clinical Research Clinical Trials Coculture Techniques Coma Complication Confocal Microscopy Data Death Rate Development Disease Edema Erythroid Experimental Models FDA approved Foundations Fright Fumarates Future Goals Health Hemorrhage Histology Histopathology Human Imaging Techniques Imaging technology Immunofluorescence Microscopy Individual Infection Inflammation Inflammatory Magnetic Resonance Imaging Malaria Measures Modeling Morbidity - disease rate Multiple Sclerosis Neuraxis Neurologic Neurologic Deficit Neurological status Nuclear Outcome Oxidative Stress Parasites Pathogenesis Pathology Pathway interactions Patients Permeability Pharmaceutical Preparations Plasmodium falciparum Pre-Clinical Model Protective Agents Proteins Public Health Reporting Research Site Spleen Stroke Techniques Testing Therapeutic Agents Therapeutic Effect Tight Junctions Up-Regulation blood-brain barrier permeabilization brain endothelial cell cytotoxic disability improved improved outcome in vitro Model insight mortality mouse model neuroimaging neuroinflammation pre-clinical protective effect survival outcome systemic inflammatory response therapeutic evaluation

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项目摘要

ABSTRACT Malaria remains a great public health challenge that has resisted worldwide control efforts. Some individuals who are infected with Plasmodium falciparum develop cerebral malaria (CM), which is associated with high morbidity and mortality despite the use of antimalarial therapy. To date, no effective adjunctive therapy is available. As brain swelling was recently identified as the main cause of death in CM, we propose to test dimethyl fumarate (DMF) to modulate neuroinflammation in an experimental cerebral malaria mouse model using histopathological and neuroimaging techniques to define its mechanisms of protection. The preliminary data demonstrate that DMF provides a survival advantage in ECM. Importantly, DMF is FDA-approved for other neuroinflammatory conditions and thus could potentially be repurposed for CM. Our long-term goal is to identify potential adjunctive therapies that reduce brain swelling and increase survival in a pre-clinical model to provide a foundation for future clinical trials and ultimately improve the outcomes of CM.

抽象的疟疾仍然是一项巨大的公共卫生挑战，它抵制了全球控制工作。一些人被恶性疟原虫感染的人会发生脑疟疾（CM），与高有关尽管使用了抗疟疾治疗，但发病率和死亡率。迄今为止，尚无有效的辅助治疗是可用的。由于最近将大脑肿胀确定为CM死亡的主要原因，因此我们建议测试二甲基富马酸（DMF）使用实验性脑疟疾小鼠模型调节神经炎症组织病理学和神经影像学技术来定义其保护机制。初步数据证明DMF在ECM中提供了生存优势。重要的是，DMF是FDA批准的神经炎症条件，因此可能会重新用于CM。我们的长期目标是确定潜在的辅助疗法可减少脑肿胀并在临床前模型中增加生存率为将来的临床试验的基础，并最终改善CM的结果。