Pathogenesis and Diagnosis

发病机制与诊断

• 批准号: 8378378
• 负责人: Sungano Mharakurwa
• 金额: $ 33.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8378378
• 关键词: Africa; African; Area; Automobile Driving; Biological Assay; Cataloging; Catalogs; Climate; Custom; Data; Diagnosis; Drug resistance; Ecology; Elements; Environment; Exhibits; Future; Gene Chips; Generic Drugs; Genes; Genetic; Genetic Polymorphism; Genetic Structures; Genetic Variation; Genome; Genomics; Genotype; Geographic Locations; Goals; Human; Immune; Immune response; Immunity; Individual; Infection; Instruction; Intervention; Laboratories; Malaria; Measurable; Measures; Modeling; Monitor; Nature; Parasites; Pathogenesis; Pharmaceutical Preparations; Plasmodium falciparum; Play; Population; Population Genetics; Prevalence; Province; Recording of previous events; Research; Resolution; Role; Sampling; Shapes; Site; Southern Africa; Structure; Surveys; Testing; Time; Ursidae Family; Validation; Virulence; Work; Zambia; Zimbabwe; base; chemotherapy; cost; cost effective; density; design; environmental change; expectation; genome-wide; innovation; insight; interest; merozoite surface protein; next generation; parasite genome; pathogen; population based; pressure; programs; response; success; tool; transmission process; vector

PROJECT SUMMARY (See instructions): The abundant geneflc diversity exhibited by P. falciparum, shaped by host and vector immunity, drug pressure, environmental change? is a key element to its success as a persistent pathogen. Understanding the nature, extent and distribution of geneflc diversity and how it changes over time will be key to devising the most efflcient and effective control measures for malaria. To date, there is no data on the population geneflcs of P. falciparium in the southern region of Africa. The overall goal of Research Area C is to establish regional proflles of the populaflon geneflcs of P. falciparium in the ICEMR study sites. This will be accomplished using array-based and PCR-based approaches that will provide both high- and low-resoluflon profiles of parasite genetic diversity. In addition to population-based issues, the proven merozoite surface protein-2 (msp2) genotyping assay will be used to assess intra-individual parasite diversity with special emphasis in asymptomatic/silent infection in areas of low transmission. Aim 1) Obtain a high-resolution profile ofthe genotypic differences between parasite isolates within and behween ICEMR study sites in order to establish the nature and scope of parasite genetic diversity. A high-density P. falciparum tiling array on the Affymetrix platform will be used for these studies. Aim 2) Implement and refine a PCR-based barcode approach as a simple, cost-effective tool for roufinely monitoring changes in the genetic structure of parasite populations in the ICEMR study sites. The barcode will consist of -25 SNPs defined by real time RT PCR. While the barcode will provide a lower resolution genotype than the array-based approach, its lower cost and ease of use will allow a much more comprehensive profile of regional populafion geneflc structure that will facilitate the identiflcation of changes over time due to control measures or other factors. Aim 3) Determine the level and dynamics of parasite clonal diversity within individuals residing in low- and high-transmission areas in the ICEMR study sites. Mulflplicity of infecflon (MOI) will be assessed based on the detecflon of polymorphisms in the msp2 gene by PCR. Special emphasis will be placed on asymptomaflc and silent infecflons and the role that these individuals may have in transmission. The expectaflon is that the genotyping and MOI data will be used to create models for predicflon of geneflc diversity influence upon transmission dynamics, drug treatment efforts, and pathogenesis.

项目总结（见说明）： 恶性疟原虫具有丰富的基因多样性，这是由宿主和媒介免疫、药物 压力，环境变化？是它成功成为持久性病原体的关键因素理解 基因多样性的性质、程度和分布，以及它如何随时间变化，将是设计 最有效的疟疾防治措施。到目前为止，没有关于人口的数据。 非洲南部地区的恶性疟原虫基因组。C研究区的总体目标是 建立ICEMR研究点恶性疟原虫群体基因型的区域分布。这将是 使用基于阵列和基于PCR的方法完成，这些方法将提供高分辨率和低分辨率 寄生虫遗传多样性概况。除了基于种群的问题，已证实的裂殖子表面 蛋白-2（msp 2）基因分型试验将用于评估个体内寄生虫多样性， 强调低传播地区的无症状/隐性感染。目标1）获得高分辨率 ICEMR研究中心内和研究中心之间寄生虫分离株之间的基因型差异概况， 确定寄生虫遗传多样性的性质和范围。一个高密度的恶性疟原虫平铺阵列上的 这些研究将使用Affyoung平台。目标2）实现和改进基于PCR的条形码 作为一种简单、成本效益高的工具，用于粗略监测寄生虫遗传结构的变化 ICEMR研究中心的人群。条形码将由通过真实的时间RT PCR定义的~ 25个SNP组成。 虽然条形码将提供比基于阵列的方法更低分辨率的基因型，但其更低的成本和 易于使用将允许更全面地了解区域人口结构， 便于识别由于控制措施或其他因素而导致的长期变化。目标3）确定 寄生虫克隆多样性的水平和动态的个人居住在低和高传播 ICEMR研究中心的区域。将根据以下物质的检测结果评估感染氟龙（MOI）的多重性 PCR检测msp 2基因多态性。特别强调的是渐近线和无声 感染和这些人在传播中可能发挥的作用。预期的结果是， 基因分型和MOI数据将用于建立预测基因多样性影响的模型， 传播动态、药物治疗工作和发病机制。