Defining the mechanism of coma in cerebral malaria

定义脑型疟疾昏迷的机制

基本信息

批准号：
10445719
负责人：
Johanna Patricia Daily
金额：
$ 52.93万
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：
2022
资助国家：
美国
起止时间：
2022-07-08 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445719
关键词：
Affect African Amino Acids Animal Model Animals Antimalarials Biological Markers Biology Blood Blood - brain barrier anatomy Brain Cerebral Malaria Cerebrospinal Fluid Child Childhood Clinical Cohort Studies Coma Complication Conscious Development Disease Encephalopathies Erythrocytes Etiology Extracellular Matrix Future GABA Receptor Goals Health Human In Vitro Individual Infection Intervention Kidney Failure Knock-out Knowledge Lysine Lysine Degradation Pathway Malaria Mammalian Cell Measures Metabolic Metabolic Pathway Metabolism Modeling Morbidity - disease rate Mus Neuraxis Neurologic Neurologic Effect Neurosciences Outcome Oxidative Stress Parasitemia Parasites Pathway interactions Patients Pipecolic Acids Plasma Plasmodium Plasmodium falciparum Plasmodium falciparum genome Play Production Public Health Rattus Reactive Oxygen Species Research Rodent Rodent Model Role Saccharopine Dehydrogenases Survivors System Testing Time Unconscious State Wakefulness base biological adaptation to stress biological systems enzyme pathway gamma-Aminobutyric Acid hypnotic improved in vivo knock-down mortality mouse model mutant neuroregulation novel receptor saccharopine

项目摘要

ABSTRACT Malaria remains a significant public health challenge that has resisted worldwide control efforts. Some individuals who become infected with Plasmodium falciparum develop cerebral malaria (CM), which presents as a coma and is associated with high morbidity and mortality. The etiology of CM coma, which is reversible in survivors, remains unknown. We have identified high blood levels of pipecolic acid (PA) in children with CM compared to mild malaria. PA has been shown to induce coma in animal models, and we will test the hypothesis that high blood levels in CM result in abnormally elevated PA central nervous system (CNS) concentrations to result coma in CM. We will determine if PA cerebral spinal fluids are elevated in CM compared with defined non-CM cases of encephalopathy. We will determine if PA is enriched in the brain of mice in infected with P. berghei ANKA in the experimental cerebral malaria model and not in the brains of mice infected with strains P. yoelii and P. chabaudi, which are infection models where mice maintain wakefulness. We will investigate the hypothesis that PA reduces consciousness through γ-aminobutyric acid (GABA) receptors, which has been suggested by prior studies using a rat model. PA has been shown by multiple groups including ours to be produced by Plasmodium, and its role in parasite biology is unknown. We will define the metabolic pathway that produces PA and test whether PA protects the malaria parasite from oxidative stress, similar to its protective role observed in mammalian cells. Overall, our goals are to define the role of PA in coma induction and parasite biology to characterize a novel mechanism of coma in humans, potentially identify a biomarker of CM etiology of coma, and characterize a potential novel target for improving the health outcomes of CM.

抽象的疟疾仍然是一项重大的公共卫生挑战，它抵制了全球控制工作。一些人他被恶性疟原虫感染了脑疟疾（cm），以昏迷状态感染并与高发病率和死亡率有关。商业昏迷的病因，幸存者是可逆的，仍然未知。我们已经确定了CM儿童的高血液饮食酸（PA）与温和的疟疾。 PA已显示出在动物模型中诱发昏迷，我们将检验以下假设。 CM的血液水平导致绝对升高的PA中枢神经系统（CNS）浓度导致昏迷在CM中。我们将确定与定义的非CM病例相比，CM的脑脊液是否升高脑病。我们将确定PA在感染了伯格氏假霉菌的小鼠大脑中是否富含PA 实验性脑疟疾模型，而不是感染菌株的小鼠大脑。 Chabaudi，是小鼠保持清醒的感染模型。我们将研究以下假设 PA通过γ-氨基丁酸（GABA）受体降低意识，这是由先验提出的使用大鼠模型的研究。 PA已由多个组显示，包括我们的疟原虫生产，它在寄生虫生物学中的作用尚不清楚。我们将定义产生PA和测试的代谢途径 PA是否保护疟疾寄生虫免受氧化应激，类似于其在哺乳动物细胞。总体而言，我们的目标是将PA在昏迷和寄生虫生物学中的作用定义表征人类昏迷的一种新型机制，有可能确定昏迷商业病因的生物标志物，并描述了改善广告健康结果的潜在新颖目标。