Chemokines in Zambian children with Cerebral Malaria

赞比亚脑型疟疾儿童的趋化因子

• 批准号: 8408862
• 负责人: MONIQUE F STINS
• 金额: $ 13.24万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-24 至 2015-09-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8408862
• 关键词: Acute; Adherence; Affect; African; Antimalarials; Apical; Attention; Autopsy; Baltimore; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Cerebral Edema; Cerebral Malaria; Cerebrospinal Fluid; Cerebrum; Child; Clinical; Clinical Data; Collaborations; Coma; Conscious; DNA; Data; Delirium; Development; Endothelial Cells; Endothelium; Erythrocytes; Event; Functional disorder; Future; Genetic Transcription; Human; Hyperactive behavior; Immune system; In Vitro; Incidence; Infection; Intracranial Hypertension; Invaded; Knowledge; Lead; Learning Disabilities; Life; Longevity; Longitudinal Studies; Malaria; Measures; Mediating; Metabolic; Modeling; Neuraxis; Neurologic; Neurologic Deficit; Neurologic Dysfunctions; Neurologic Manifestations; Neurologic Symptoms; Neuronal Dysfunction; Neurons; Parasitemia; Parasites; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Persons; Phase; Plasma; Plasmodium; Plasmodium falciparum; Play; Province; Publishing; Recording of previous events; Recurrence; Research; Role; Sampling; Seizures; Severities; Severity of illness; Side; Solid; Staging; Swelling; Symptoms; Syndrome; Teaching Hospitals; Therapeutic; Therapeutic Intervention; United States National Institutes of Health; Universities; University Hospitals; Zambia; base; brain tissue; chemokine; cognitive function; cytokine; follow-up; immunological status; improved; in vitro Model; in vivo; medical schools; mortality; new therapeutic target; novel; prevent; prognostic; programs; public health relevance; repository

DESCRIPTION (provided by applicant): Cerebral malaria (CM) is a clinical syndrome associated with Plasmodium falciparum infection that is associated with a high mortality of up to 30%, particular in children. Neurological symptoms and signs include impaired consciousness, coma, delirium, seizures, and increased intracranial hypertension. It has recently become apparent that in African children, persistent neurologic deficits, including recurrent seizures and learning disabilities occur after survival of CM episodes. Central to P. falciparum pathophysiology is sequestration of trophozoite and schizont stages of P. falciparum-infected red blood cells (Pf-IRBC) to the brain blood vessel endothelium. Plasmodium differs from other neuropathogens that invade the brain as Pf-IRBC do NOT cross the blood-brain barrier (BBB) into the central nervous system, but are still able to elicit neuronal dysfunction, as observed in P. falciparum CM. It is not known how a parasite, inside an erythrocyte and confined to the blood vessels, is able to induce the neurological signs and symptoms associated with CM. Since the BBB endothelium is located at the interface of these events, we hypothesize that activation of BBB endothelium plays a role in conferring neurological dysfunction. Our published and preliminary data with an in vitro human BBB model show that in CM, the BBB endothelium responds with increased transcription and release of large amounts of cyto- and chemokines towards the brain side and that this that may be responsible and/or contribute significantly to the observed neurological dysfunction in CM. To verify and validate these in vitro findings for the human situation and to assess whether the BBB endothelium would be an appropriate target for adjunctive therapeutic treatment and to prevent neurologic sequelae, it is proposed to assess a specific cyto- chemokine profile in the CSF of CM patients. To accomplish this, we propose a collaboration with the University Hospital of Zambia, Lusaka, Zambia. This is an initial R21 research and capacity building proposal to the NIH Fogarty Program "Brain Disorders in the Developing World: Research across the lifespan". We intend to set the basis for an extended future collaboration that will focus on the role of chemokines in CM-mediated neurological dysfunction, how this affects a patient's life and development, and how the neurologic sequelae can be prevented in the future.

描述（由申请人提供）：脑型疟疾 (CM) 是一种与恶性疟原虫感染相关的临床综合征，死亡率高达 30%，尤其是儿童。神经系统症状和体征包括意识障碍、昏迷、谵妄、癫痫发作和颅内高压升高。最近很明显，非洲儿童存在持续性神经功能缺陷，包括反复发作和癫痫发作。 CM 发作后出现学习障碍。恶性疟原虫病理生理学的核心是将恶性疟原虫感染的红细胞（Pf-IRBC）的滋养体和裂殖体阶段隔离到脑血管内皮。疟原虫与侵入大脑的其他神经病原体不同，因为 Pf-IRBC 不会穿过血脑屏障 (BBB) 进入中枢神经系统，但仍能够引起神经元功能障碍，如在恶性疟原虫 CM 中观察到的那样。目前尚不清楚红细胞内并局限于血管内的寄生虫如何诱发与 CM 相关的神经体征和症状。由于 BBB 内皮位于这些事件的界面，我们假设 BBB 内皮的激活在导致神经功能障碍中发挥作用。我们发表的体外人类 BBB 模型的初步数据表明，在 CM 中，BBB 内皮细胞的反应是转录增加，并向大脑侧释放大量细胞因子和趋化因子，这可能是造成和/或显着贡献的原因。到 观察到 CM 中的神经功能障碍。为了验证和验证这些针对人类情况的体外研究结果，并评估 BBB 内皮是否是辅助治疗的适当靶点并预防神经系统后遗症，建议评估 CM 脑脊液中的特定细胞趋化因子谱患者。为了实现这一目标，我们提议与赞比亚卢萨卡的赞比亚大学医院合作。这是 NIH Fogarty 项目“发展中国家的脑部疾病：整个生命周期的研究”的初步 R21 研究和能力建设提案。我们打算为未来的扩展合作奠定基础，重点关注趋化因子在 CM 介导的神经功能障碍中的作用、这如何影响患者的生活和发育，以及未来如何预防神经系统后遗症。