Microfluidic platforms for severe malaria

用于严重疟疾的微流控平台

• 批准号: 7019063
• 负责人: PRADIPSINH K. RATHOD
• 金额: $ 19.93万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7019063
• 关键词: Plasmodium falciparum; antimalarial agents; blood flow measurement; blood vessel occlusion; capillary; cell morphology; clinical research; drug screening /evaluation; erythrocytes; hemodynamics; human tissue; malaria; membrane permeability; microfluidics; model design /development

DESCRIPTION (provided by applicant): Severe malaria caused by the parasite Plasmodium falciparum is a potentially fatal disease, in part due to the failure of host organs brought about by the accumulation of parasitized red blood cells in the microvasculature. Capillary blockage is associated with the loss of deformability of infected erythrocytes, and in the past, progress in understanding the pathophysiology of these rigidified erythrocytes has been made either by examining postmortem biopsies or by in vitro adhesion studies of suspended infected cells. The PI and colleagues have demonstrated how simple microfluidic devices allow modeling of malaria pathogenesis under controlled laboratory conditions (Shelby et al., 2003, PNAS, 100: 14618-14622). The utility of more advanced microfluidic tools to mimic the mixed cellular environment of capillaries can be tested in relation to two important issues in severe malaria: First, anti-malarial compounds may be prioritized based on their ability to clear obstructed capillaries, not just their antiproliferative activity. Second, parasite clearance by cells of the immune system can be studied under flow and capillary constrictions, which may help understand natural immunity. The defined goal of this R21 project is to develop targeted microfluidic devices for severe malaria: Specific aim I: Evaluate the effect of anti-malarial drugs on clearing capillary obstructions. 1.1. Fabricate microfluidic platforms for the controlled delivery of drugs into a model obstruction. 1.2. Develop high throughput assays for identifying compounds that affect red blood cell deformability. 1.3. Characterize the most promising experimental drugs under fluid flow. Specific aim II: Evaluate phagocytosis of P. falciparum-infected erythrocytes under flow. 2.1. Fabricate microfluidic channels that support host cells. 2.2. Measure phagocytosis in microfluidic channels. 2.3. Develop a model to study pitting in obstructed capillaries. In the future, the devices developed here may also find utility in studying adhesion and natural immunity in malaria, and in control of other infectious diseases.

描述（由申请人提供）：恶性疟原虫引起的严重疟疾是一种潜在的致命疾病，部分原因是宿主器官失败了，这是由于微胚膜中寄生的红细胞的积累而导致的。毛细血管阻塞与感染红细胞的可变形性丧失有关，并且过去，通过检查验尸活检或通过对悬浮感染细胞的体外粘附研究进行研究，了解这些刚性红细胞的病理生理学的进展。 pi 同事证明了简单的微流体设备如何在受控实验室条件下建模疟疾发病机理（Shelby等，2003，PNAS，100：14618-14622）。更先进的微流体工具可以根据严重疟疾中的两个重要问题进行测试模仿毛细血管的混合细胞环境的实用性：首先，可以根据清除阻塞性毛细血管的能力来优先考虑抗疟疾化合物，而不仅仅是其抗增殖活性。其次，可以在流动和毛细收缩下研究细胞对免疫系统的寄生虫清除，这可能有助于理解自然免疫力。该R21项目的定义目标是开发针对严重疟疾的靶向微流体设备：具体目的I：评估抗疟疾药物对清除毛细血管阻塞的影响。 1.1。制造微流体平台，以将药物控制到模型阻塞中。 1.2。开发高通量测定法，以识别影响红细胞可变形性的化合物。 1.3。表征流体流动下最有希望的实验药物。特定目标II：评估流动下的恶性疟原虫感染的红细胞的吞噬作用。 2.1。制造支持宿主细胞的微流体通道。 2.2。测量微流体通道中的吞噬作用。 2.3。开发一个模型来研究阻塞的毛细血管中的蚀点。将来，这里开发的设备还可能发现疟疾中的粘附和自然免疫力以及控制其他传染病的效用。