Pathogenesis and Diagnosis

发病机制与诊断

• 批准号: 8503400
• 负责人: Sungano Mharakurwa
• 金额: $ 29.16万
• 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/8503400
• 关键词: Africa; African; Area; Automobile Driving; Bar Codes; 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; Patients; Pharmaceutical Preparations; Plasmodium falciparum; Play; Polymorphism Analysis; Population; Population Genetics; Prevalence; Province; Recording of previous events; Research; Resolution; Role; Sampling; Shapes; Site; Southern Africa; Surveys; Testing; Time; Ursidae Family; Validation; Virulence; Work; Zambia; Zimbabwe; base; chemotherapy; cost; cost effective; density; design; environmental change; expectation; genome-wide; innovation; insertion/deletion mutation; insight; interest; merozoite surface protein; next generation; parasite genome; pathogen; population based; population genetic structure; pressure; programs; response; success; tool; transmission process; vector

PROJECT SUMMARY (See instructions): The abundant genetic 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 genetic diversity and how it changes over time will be key to devising the most efficient and effective control measures for malaria. To date, there is no data on the population genetics of P. falciparium in the southern region of Africa. The overall goal of Research Area C is to establish regional profiles of the population genetics 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-resolution 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 between 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 routinely 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 population genetic structure that will facilitate the identification 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. Multiplicity of infection (MOI) will be assessed based on the detection of polymorphisms in the msp2 gene by PCR. Special emphasis will be placed on asymptomatic and silent infections and the role that these individuals may have in transmission. The expectatoin is that the genotyping and MOI data will be used to create models for prediction of genetic diversity influence upon transmission dynamics, drug treatment efforts, and pathogenesis

项目摘要（参见说明）：恶性疟原虫表现出的丰富遗传多样性是由宿主和媒介免疫、药物压力、环境变化形成的？是其作为持久性病原体成功的关键因素。了解遗传多样性的性质、范围和分布以及它如何随时间变化将是制定最有效的疟疾控制措施的关键。迄今为止，尚无非洲南部地区恶性疟原虫群体遗传学的数据。研究领域 C 的总体目标是建立 ICEMR 研究地点恶性疟原虫群体遗传学的区域概况。这将通过基于阵列和基于 PCR 的方法来实现，这些方法将提供寄生虫遗传多样性的高分辨率和低分辨率图谱。除了基于人群的问题外，经过验证的裂殖子表面蛋白 2 (msp2) 基因分型测定将用于评估个体内寄生虫多样性，特别强调低传播地区的无症状/无症状感染。目标 1) 获得 ICEMR 研究地点内和之间的寄生虫分离株之间基因型差异的高分辨率概况，以确定寄生虫遗传多样性的性质和范围。 Affymetrix 平台上的高密度恶性疟原虫平铺阵列将用于这些研究。目标 2) 实施和完善基于 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 ICEMR 研究地点寄生虫种群遗传结构的变化。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，但其较低的成本和易用性将允许更全面地了解区域群体遗传结构，这将有助于识别由于控制措施或其他措施而随时间发生的变化。因素。目标 3) 确定 ICEMR 研究地点居住在低传播和高传播区域的个体体内寄生虫克隆多样性的水平和动态。将根据 PCR 检测 msp2 基因的多态性来评估感染复数 (MOI)。将特别强调无症状和无症状感染以及这些人在传播中可能发挥的作用。期望基因分型和 MOI 数据将用于创建模型来预测遗传多样性对传播动力学、药物治疗工作和发病机制的影响