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.

项目摘要（参见说明）： 恶性疟原虫表现出丰富的基因多样性，由宿主和载体免疫、药物形成 压力、环境变化？是其作为持久性病原体成功的关键因素。理解 基因多样性的性质、范围和分布以及它如何随时间变化将是设计的关键 最有效、最有效的疟疾控制措施。迄今为止，尚无人口数据 非洲南部地区恶性疟原虫的基因。研究领域C的总体目标是 建立 ICEMR 研究地点恶性疟原虫种群基因的区域概况。这将是 使用基于阵列和基于 PCR 的方法完成，该方法将提供高分辨率和低分辨率 寄生虫遗传多样性概况。除了基于人口的问题外，已证实的裂殖子表面 蛋白质 2 (msp2) 基因分型测定将用于评估个体内寄生虫多样性 重点关注低传播地区的无症状/无症状感染。目标1）获得高分辨率 ICEMR 研究地点内部和之间的寄生虫分离株之间的基因型差异概况（按顺序排列） 确定寄生虫遗传多样性的性质和范围。高密度恶性疟原虫平铺阵列 Affymetrix 平台将用于这些研究。目标 2) 实施并完善基于 PCR 的条形码 方法作为一种简单、经济高效的工具，用于定期监测寄生虫遗传结构的变化 ICEMR 研究地点的人群。条形码将由实时 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分辨率更低的基因型，但其成本更低并且 易于使用将能够更全面地了解区域人口基因结构，这将 便于识别由于控制措施或其他因素而随时间发生的变化。目标 3) 确定 低传播和高传播个体体内寄生虫克隆多样性的水平和动态 ICEMR 研究地点的区域。感染复数 (MOI) 将根据检测到的情况进行评估 通过 PCR 检测 msp2 基因的多态性。将特别强调无症状和沉默者 感染以及这些人在传播中可能发挥的作用。期望的是 基因分型和 MOI 数据将用于创建预测基因多样性影响的模型 传播动力学、药物治疗努力和发病机制。