Defining the mechanism of coma in cerebral malaria

定义脑型疟疾昏迷的机制

• 批准号: 10662496
• 负责人: Johanna Patricia Daily
• 金额: $ 54.05万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/10662496
• 关键词: Affect; African; Amino Acids; Animal Model; Animals; Antimalarials; Biological Markers; Biology; Blood; Brain; Central Nervous System; Cerebral Malaria; Cerebrospinal Fluid; Child; Childhood; Clinical; Cohort Studies; Collaborations; Coma; Complication; Conscious; Development; Disease; Encephalopathies; Erythrocytes; Etiology; Extracellular Matrix; Future; 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; 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; biological adaptation to stress; biological systems; blood-brain barrier crossing; enzyme pathway; gamma-Aminobutyric Acid; hypnotic; improved; in vivo; knock-down; mortality; mouse model; mutant; neuroregulation; novel; receptor; saccharopine

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 疟疾仍然是一个重大的公共卫生挑战，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)，表现为昏迷状态 并与高发病率和死亡率相关。 CM 昏迷的病因在幸存者中是可逆的， 仍然未知。我们发现，与其他儿童相比，患有 CM 的儿童血液中哌可酸 (PA) 水平较高 轻度疟疾。 PA 已被证明会在动物模型中诱发昏迷，我们将检验高浓度 PA 的假设 CM 中的血液浓度导致 PA 中枢神经系统 (CNS) 浓度异常升高，从而导致昏迷 在厘米。我们将确定 CM 患者的 PA 脑脊液是否比确定的非 CM 病例升高 脑病。我们将确定感染伯氏疟原虫 ANKA 的小鼠大脑中 PA 是否富集 实验性脑型疟疾模型，而不是感染约氏疟原虫和疟原虫菌株的小鼠大脑中。 chabaudi，这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，这已被先前的研究表明 使用大鼠模型进行研究。包括我们在内的多个团体已证明 PA 是由 Plasmodium 生产的， 它在寄生虫生物学中的作用尚不清楚。我们将定义产生 PA 的代谢途径并进行测试 PA 是否可以保护疟原虫免受氧化应激，类似于在 哺乳动物细胞。总体而言，我们的目标是确定 PA 在昏迷诱导和寄生虫生物学中的作用，以 描述人类昏迷的新机制，有可能识别昏迷的 CM 病因学生物标志物， 并描述了改善 CM 健康结果的潜在新目标。