Red cell determinants of premature hemolysis of Plasmodium infected red cells

疟原虫感染的红细胞过早溶血的红细胞决定因素

• 批准号: 9754653
• 负责人: Martha Ann Clark
• 金额: $ 6.77万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754653
• 关键词: Affect; Antimalarials; Biological Assay; Blood; Cell Volumes; Cell physiology; Cells; Cellular Stress; Cellular biology; Cessation of life; Cytolysis; Cytoskeleton; Daughter; Digestion; Disease; Erythroblasts; Erythrocytes; Gene Expression; Genes; Genetic Polymorphism; Genetic Screening; Glucosephosphate Dehydrogenase Deficiency; Goals; Health; Hematopoietic stem cells; Hemoglobin; Hemoglobinopathies; Hemolysis; Heterogeneity; Hour; Human; In Vitro; Individual; Infection; Liver; Malaria; Membrane; Mentors; Molecular; Osmotic Fragility test; Parasites; Parasitic infection; Pathway interactions; Permeability; Physiology; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Play; Population; Predisposition; Public Health; Public Health Schools; RNA Interference; Regulation; Research; Resources; Reticulocytes; Role; Scientist; Seeds; Sickle Cell; Structure; Symptoms; System; Therapeutic; Variant; Virulent; cell age; experimental study; forward genetics; improved; knock-down; malaria infection; novel; premature; programs; pyruvate kinase deficiency; small hairpin RNA; small molecule; therapeutic target

Project Summary With 250 million infections and 500,000 deaths attributed to malaria each year, malaria is a significant burden on public health in the developing world. Of the five species of malaria that infect humans, Plasmodium vivax is the most globally widespread. The long-term objective of this study is to investigate the influence red cell physiology has on the survival of blood stage Plasmodium. The blood stage of P. vivax infection is responsible for all symptoms of disease, and is the reservoir from which the transmitted gametocyte stage emerges. Upon infecting a host red cell, P. vivax need the host red cell to remain in tact for the two days required for the parasite to produce the daughter merozoites that will initiate the next round of blood stage infection. A growing body of evidence suggests that the malaria parasites excessive digestion of host hemoglobin and new permeability pathways (NPPs) are responsible for maintaining the osmotic stability of the infected red cell. The impact host red cell physiology has on the osmotic stability of P. vivax infected red cells is not known. In this proposal, I will characterize the osmotic stability of uninfected and P. vivax infected nucleated red cell precursors and reticulocytes with small molecules (Aim 1), and I will identify red cell factors that determine premature hemolysis of P. vivax infected red cells with a forward genetic screen (Aim 2). The experiments proposed in this study have the potential to reveal a novel host antimalarial mechanism, therapeutic targets for the virulent blood stage of malaria infection, and may facilitate the adaptation of P. vivax to long term in vitro culture.

项目摘要 每年有2.5亿人感染疟疾，50万人死于疟疾，疟疾是一个重大负担 关于发展中国家的公共卫生。在感染人类的五种疟疾中，间日疟原虫是 是全球分布最广的。这项研究的长期目标是研究对红细胞的影响 生理上对血液期疟原虫的存活有影响。间日疟原虫感染的血液期是主要原因 对于疾病的所有症状，它是传递的配子体阶段出现的蓄水池。vt.在.的基础上 感染宿主红细胞，间日疟原虫需要宿主红细胞保持正常状态两天，这是 寄生虫产生的女儿裂殖子将引发下一轮血液期感染。一个不断增长的 大量证据表明，疟疾寄生虫过度消化宿主的血红蛋白和新的 通透通路(NPP)负责维持受感染红细胞的渗透稳定性。这个 宿主红细胞生理对间日疟原虫感染红细胞渗透稳定性的影响尚不清楚。在这 建议，我将表征未感染和间日疟原虫感染的有核红细胞的渗透稳定性 前体和小分子网织红细胞(目标1)，我将确定决定 用正向遗传筛选法检测感染间日疟原虫的红细胞的过早溶血(目标2)。这些实验 在这项研究中提出的有可能揭示一种新的宿主抗疟疾机制，治疗靶点 疟疾感染的毒血阶段，并可能促进间日疟原虫在体外长期适应 文化。