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

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个巨大的公共卫生挑战，一直阻碍着全世界的控制努力。一些个人感染恶性疟原虫的人会患上脑型疟疾（CM），这种疾病与高发病率有关。尽管使用抗疟疾治疗，发病率和死亡率仍然很高。迄今为止，尚无有效的辅助治疗方法可用的。由于脑肿胀最近被确定为 CM 死亡的主要原因，我们建议测试二甲基富马酸（DMF）调节实验性脑疟疾小鼠模型中的神经炎症组织病理学和神经影像技术来定义其保护机制。初步数据证明 DMF 在 ECM 中具有生存优势。重要的是，DMF 已获得 FDA 批准用于其他用途神经炎症性疾病，因此有可能重新用于 CM。我们的长期目标是确定在临床前模型中减少脑肿胀并提高生存率的潜在辅助疗法为未来的临床试验奠定基础，并最终改善 CM 的结果。