Plasmodium falciparum gametocytogenesis

恶性疟原虫配子细胞发生

基本信息

批准号：
9171415
负责人：
Kim C Williamson
金额：
$ 35.91万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9171415
关键词：
Affect Age Antibodies Appearance Artemisinins Basic Science Biological Assay Bite Blood Blood specimen Cells Cessation of life Clinical Combined Modality Therapy Complement Culicidae DNA Data Development Disease Erythrocytes Evaluation Exposure to Funding Future Genes Genetic Transcription Genotype Giemsa stain Goals Harvest Health Hematocrit procedure Hemoglobin Human Immune Immune response Immunity In Vitro Individual Infection Integration Host Factors Intervention Invaded Lead Life Cycle Stages Malaria Measures Methods Molecular Molecular Analysis Molecular Profiling Monitor Nucleic Acids Parasitemia Parasites Pathway interactions Patient Monitoring Patients Pattern Persons Plasma Plasmodium Plasmodium falciparum Population Predictive Value Prevalence Production RNA Reporting Role Sampling Signal Pathway Source Staging System Testing Time Vaccination Work artemisinine asexual base cohort cytokine design follow-up in vivo killings sexual debut tissue culture transmission process

项目摘要

DESCRIPTION (provided by applicant): For malaria to be spread from person to person via a mosquito, Plasmodium parasites must undergo sexual differentiation to form gametocytes. Although an essential part of the life cycle, little is known about the production of these stages n vitro or in vivo, which complicates the development of strategies that effectively block transmission. In the previous funding period we identified a gene that is critical for gametocyte production, P. falciparum gametocyte development 1 (Pfgdv1) and the set of genes specifically expressed during early gametocytogenesis in P. falciparum (Pfge genes). Analysis of the expression profiles of these genes in vitro and in a cohort of malaria infected patients lead to th hypothesis that gametocytes are formed during each asexual cycle as part of normal development. This type of continuous gametocyte production would provide a consistent source of infectious parasites whenever a mosquito bites. However, it also has serious implications for the design of control measures and suggests that mass treatment or vaccination would be needed to eliminate the parasite. To further evaluate the initiation of gametocytogenesis in vivo, we developed a method to directly compare asexual parasitemia and gametocyte commitment in blood samples from patients. The relationship between gametocyte induction and maturation in vivo is needed to understand the factors that contribute to the production of infectious gametocytes. Aim one will evaluate the role of patient age and hematocrit in gametocyte production, while Aims 2 and 3 will use molecular (Aim 2) and immunological (Aim 3) to understand the role of parasite exposure and immune stimulation on gametocyte commitment and maturation. This field work will complement our ongoing basic research defining the molecular basis for gametocytogenesis. Together the work will extend our understanding of the initiation and formation gametocytes that are essential for the spread of malaria. The findings should provide markers to identify gametocyte carriers before they are infectious and identify signaling pathways that could be targeted to block transmission.

描述（由申请人提供）：要通过蚊子通过蚊子传播疟疾，疟原虫必须进行性差异化才能形成配子细胞。尽管对生命周期的重要组成部分，但对这些阶段的产生n Bitter或In Vivo知之甚少，这使得有效阻止传播的策略的发展变得复杂。在上一个资金期间，我们确定了一个对配子细胞生产至关重要的基因，恶性疟原虫配子型发育1（PFGDV1）以及在恶性疟原虫早期Gametocypopeneseration期间特异性表达的基因集（PFGE基因）。分析这些基因在体外和一系列疟疾感染患者中的表达谱分析导致假设在每个无性循环中形成了配子细胞，这是正常发育的一部分。每当蚊子叮咬时，这种连续的配子细胞产生将提供一致的感染性寄生虫来源。但是，它对控制措施的设计也有严重的影响，并表明需要进行大规模治疗或疫苗接种以消除寄生虫。为了进一步评估体内配子细胞生成的启动，我们开发了一种直接比较患者血液样本中无性寄生虫血症和配子细胞承诺的方法。需要在体内诱导和成熟之间的关系来了解有助于产生传染性配子细胞的因素。 AIM ONE将评估患者年龄和血细胞比容在配子细胞产生中的作用，而AIM 2和3将使用分子（AIM 2）和免疫学（AIM 3）来了解寄生虫暴露和免疫刺激对配子细胞的承诺和成熟的作用。这项现场工作将补充我们正在进行的基础研究，以定义了配子细胞发生的分子基础。这项工作将扩大我们对疟疾传播至关重要的启动和形成配子细胞的理解。这些发现应提供标记以识别配子载体载体在传染性之前，并识别可以针对阻止传输的信号通路。