Understanding how the brain recovers from cerebral malaria

脑型疟疾是疟疾的一种毁灭性并发症，每年造成数十万儿童死亡和残疾。目前，除了抗疟疾药物之外，还没有针对CM的特异性治疗方法，这是一种效果有限的次优治疗方法，无法防止很大比例的患者死亡或残疾。事实上，目前有20%的人死于CM， 15-30%的幸存者表现出严重的长期神经系统并发症。至关重要的是，近年来在减少疟疾发病率方面取得的进展停滞不前，人们越来越关注耐药寄生虫在世界不同地区的发展和传播。因此，迫切需要新的治疗方法，以减少一般影响撒哈拉以南发展中国家脆弱社区的慢性慢性疾病对健康和社会经济的影响。在CM期间，血液来源的液体泄漏到大脑中，导致大脑肿胀。这会导致颅内压升高，这可能是致命的，或者会导致大脑结构损伤，对幸存者造成长期的脑损伤。此外，在CM过程中，血源性液体不受控制地进入大脑，将有害的寄生虫和宿主免疫物质带入敏感的脑组织，从而导致严重的脑部炎症。随后失去严格调节和平衡的大脑环境，导致大脑功能受损和严重的神经紊乱。因此，多发性硬化症的恢复取决于液体和血液来源的物质从患者的大脑中排出的速度，以及脑组织被清洁的速度，以重建必要的健康的大脑环境。目前我们不知道这些事件是如何协调的。在这个应用程序中，我们计划使用一个我们已经广泛验证的实验性小鼠CM模型，结合各种互补的神经成像技术，以确定在CM恢复过程中流体和分子从大脑排出的特定途径。在本申请的目标1中，我们将直接解决CM抗疟疾药物治疗后液体和物质离开大脑的途径，我们将评估这些途径是否被CM破坏，从而影响大脑从综合征中恢复的速度和效率。我们将采用各种技术来积极和消极地影响CM恢复期间的脑引流途径，以确定这些过程的治疗靶向是否是CM综合征的潜在新疗法。在CM恢复过程中，由于血液来源的液体从大脑中排出，因此必须积极地将其他血液来源的物质和废物从大脑中排出，以完全恢复大脑健康。因此，在目标2中，我们将评估在CM恢复期间从大脑中清除液体和分子的途径如何与清洁大脑以使其恢复健康的过程相互关联。具体来说，我们将讨论脑脊液是如何在CM恢复过程中通过脑组织灌注的，以及这是如何抑制大脑炎症、重建神经元信号和恢复大脑功能所必需的。该项目的完成将使我们对CM后控制大脑恢复的过程的理解发生重大变化，并将为这种毁灭性疾病揭示新的潜在治疗方法。重要的是，脑引流的途径，以及它们如何受到疾病的调节和影响，目前是其他脑部疾病（如阿尔茨海默病、中风和创伤性脑损伤）的主要研究领域。因此，这个项目的结果将对疟疾社区以外的领域产生影响，并将对更广泛的神经科学界以及我们对如何治疗脑部疾病的理解产生重大影响。

Cerebral malaria (CM) is a devastating complication of malaria that is responsible for the death and disability of hundreds of thousands of children, each year. At present there is no specific treatment for CM other than anti-malarial drugs, which is a sub-optimal treatment with limited effectiveness that fails to prevent death or disability in a high proportion of sufferers. Indeed, currently 20% of individuals die of CM and 15-30% of survivors exhibit severe long-lasting neurological complications. Critically, in recent years progress towards reducing the incidence of malaria has stalled and there are increasing concerns regarding the development and spread of drug-resistant parasites in different parts of the world. Therefore, new therapies to reduce the health and socio-economic impact of CM, which generally affects vulnerable communities in developing Sub-Saharan countries, are urgently needed.During CM, blood-derived fluid leaks into the brain, which causes the brain to swell. This leads to raised intracranial pressure, which can be fatal, or which can lead to structural damage to the brain that causes long lasting brain damage in survivors. Moreover, the uncontrolled entry of blood-derived fluid into the brain during CM carries noxious parasitic and host immunological materials into the sensitive cerebral tissue, which causes significant brain inflammation. The subsequent loss of the tightly regulated and balanced brain environment leads to impaired brain functionality and serious neurological disturbances. Thus, the recovery from CM depends upon how quickly fluid and blood-derived materials are drained from the brain of sufferers, and how rapidly the brain tissue can be cleansed, to reestablish the necessary healthy brain environment. At present we do not know how these events are coordinated.In this application we plan to use an experimental murine model of CM, which we have extensively validated, combined with a variety of complementary neuroimaging techniques, to identify the specific pathways through which fluid and molecules are drained from the brain during recovery from CM. In objective 1 of this application, we will directly address the routes that fluid and materials exit the brain following anti-malarial drug treatment of CM and we will assess whether these routes are compromised by CM, influencing the speed and efficiency through which the brain can recover from the syndrome. We will employ various techniques to positively and negatively influence the pathways of brain drainage during recovery from CM to identify if therapeutic targeting of these processes are potential new therapies for the CM syndrome.As the blood-derived fluid is drained from the brain during recovery from CM, other blood-derived materials and waste must be actively pushed from the brain to fully reestablish brain health. Thus, in objective 2 we will assess how the routes that remove fluid and molecules from the brain during recovery from CM are interlinked with the processes that cleanse the brain to return it to health. Specifically, we will address how cerebrospinal fluid is perfused through the brain tissue during recovery from CM and how this is required to dampen brain inflammation, re-establish neuronal signaling, and to regain brain function. The completion of this project will lead to a step change in our understanding of the processes that control the recovery of the brain following CM, and will reveal new potential therapies for the devasting condition. Importantly, the routes of brain drainage, and how they are regulated and impacted by disease, is currently a major area of research for other brain conditions, such as Alzheimer's disease, stroke and traumatic brain injury. Therefore, the results from this project will have impact beyond the malaria community and will have major relevance for the wider neuroscience community, and our understanding of how to treat brain diseases.