Dissecting the genetic complexity of artemisinin resistance

剖析青蒿素耐药性的遗传复杂性

• 批准号: 10216648
• 负责人: Michael T Ferdig
• 金额: $ 39.43万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216648
• 关键词: Affect; Africa; Africa South of the Sahara; African; Antimalarials; Artemisinins; Biological; Biological Assay; Biological Process; Chloroquine; Chloroquine resistance; Chromosome Mapping; Clinic; Complex; Data Analyses; Dose; Drug Screening; Drug Targeting; Drug resistance; Evolution; Experimental Genetics; Failure; Generations; Genes; Genetic; Genetic Crosses; Genetic Determinism; Genome; Geographic Locations; Goals; Growth; Head; Hepatocyte; Human; Knowledge; Laboratories; Lead; Link; Malaria; Maps; Measures; Metabolic Clearance Rate; Methods; Mus; Mutation; Outcome; Pan Genus; Parasites; Pathway interactions; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Policies; Population; Predisposition; Protocols documentation; Quantitative Trait Loci; Research; Resistance; Role; Series; Southeastern Asia; Structure; System; Testing; Time; Treatment Failure; Uncertainty; benflumetol; causal variant; clinical phenotype; design; driving force; drug action; drug candidate; fitness; gene discovery; gene interaction; genetic architecture; genetic linkage; indexing; mutant; novel; phenotypic data; prevent; resistance gene; resistance mechanism; resistant strain; response; success; trait; whole genome

ABSTRACT The recently identified kelch13 gene is an important marker of artemisinin resistance (ART-R) in malaria and has been linked to the slow-clearance rate (CR) clinical phenotype as well as treatment failures. In spite of this exciting discovery of a major gene affecting the trait, there are several indications that additional (or alternative) genes and gene interactions contribute to both the level of resistance, as measured by slow clearance times in the clinic and ring stage survival in the laboratory. Understanding the detailed functional role of various kelch13 mutants, their broader biological roles and functional partners, and their impact on fitness presents strategic hurdles to understanding and slowing the evolution and spread of ART-R. Recognizing that the phenotypic effect of a major resistance gene resides in a co-evolved whole-genome context, we will use quantitative trait locus (QTL) mapping combined with intensive and precise phenotyping across a set of eight inter-related experimental crosses constructed using our novel FRG huHep/huRBC mice We will use this that determine resistance and/or susceptibility to artemisinin and to partner drugs such as piperaquine and lumefantrine and to identify drug targets and susceptibility determinants for a wide range of compounds. In addition, we will examine the relationship between levels of ART-R and competitive growth in RBCs as a surrogate measure of fitness to identify the factors that will influence the spread of malarial resistance in African populations. to dissect this biological complexity. approach to find genes and pathways To identify the genes and pathways that influence the origins and spread of resistance we will (i) map the genetic determinants of ART-R to test our hypothesis that a complex genetic architecture and multiple genes are involved in ART-R, (ii) map genetic determinants of susceptibility to 24 antimalarial drugs, including the partner drugs of ART, piperiquine, along with antimalarial drugs targeting a wide range of biological processes and a set of candidate drugs for which the drug target is not known and, (iii) map the impact of ART-R on competitive growth using small volume head-to-head competitive-growth outcomes to compute a `relative fitness index' quantitative score for QTL mapping.

摘要 最近发现的kelch 13基因是疟疾中青蒿素耐药性（ART-R）的重要标志， 与缓慢清除率（CR）临床表型以及治疗失败有关。尽管如此 令人兴奋的发现影响性状的主要基因，有几个迹象表明，额外的（或替代） 基因和基因相互作用有助于耐药水平，如通过缓慢的清除时间测量的， 实验室中的临床和环期存活率。了解各种kelch的详细功能作用13 突变体，它们更广泛的生物学作用和功能伙伴，以及它们对适应性的影响， 这是理解和减缓ART-R的进化和传播的障碍。 认识到主要抗性基因的表型效应存在于共同进化的全基因组中， 在此背景下，我们将使用数量性状基因座（QTL）定位结合密集和精确的表型 在使用我们的新型FRG huHep/huRBC小鼠构建的一组八个相互关联的实验杂交中， 我们将用这个来决定 对青蒿素和伙伴药物如哌喹和苯芴醇的耐药性和/或敏感性， 以确定药物靶点和多种化合物的易感性决定因素。此外，我们会 检查ART-R水平与RBC竞争性生长之间的关系，作为替代指标， 确定将影响疟疾耐药性在非洲人群中传播的因素。 来剖析这种生物复杂性。寻找基因和途径的方法 为了确定影响耐药性起源和传播的基因和途径，我们将（i） 映射 ART-R的遗传决定因素来检验我们的假设，即复杂的遗传结构和多个基因 （ii）绘制24种抗疟药物易感性的遗传决定因素，包括 抗逆转录病毒疗法的伙伴药物哌哌喹，沿着抗疟疾药物，靶向广泛的生物过程 和一组药物靶点未知的候选药物，以及（iii）绘制ART-R对 竞争性增长使用小批量头对头竞争性增长结果来计算“相对 适合度指数的定量评分用于QTL定位。