A network-based method for predicting gene interactions in artemisinin resistance

基于网络的青蒿素抗性基因相互作用预测方法

• 批准号: 8963428
• 负责人: Michael T Ferdig
• 金额: $ 19万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-06 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963428
• 关键词: Alleles; Artemisinins; Candidate Disease Gene; Chloroquine resistance; Chloroquinoxaline Sulfonamide; Chromosomes, Human, Pair 13; Clinical; Combined Modality Therapy; Data; Development; Drug resistance; Evolution; Exhibits; Gene Expression Profile; Genes; Genetic; Genome; Genotype; Goals; Gold; Health; In Vitro; Intervention; Knowledge; Libraries; Link; Malaria; Maps; Measures; Methods; Monitor; Mutagenesis; Mutation; Myanmar; Network-based; Parasite resistance; Parasites; Pathway Analysis; Pharmaceutical Preparations; Phenotype; Physiology; Plasmodium falciparum; Population; Population Genetics; Predisposition; Resistance; Southeastern Asia; Staging; Systems Biology; Tertiary Protein Structure; Thailand; Time; Transcript; artemisinine; base; biological systems; differential expression; fitness; gene function; gene interaction; genome wide association study; genome-wide; global health; innovation; killings; mutant; novel; novel strategies; pressure; resistance mechanism; resistance mutation; response; screening; tool

 DESCRIPTION (provided by applicant): The malaria parasite, Plasmodium falciparum, continues to kill people at an alarming rate. Solving the difficult challenge of emerging resistance to artemisinin (ART)-based combination therapies will take the full set of traditional and innovative new tools. An exciting recent discovery pinpointed mutations in a chromosome 13 gene that encodes a kelch propeller domain as a marker for emerging ART-resistance (ART-R), however nothing is known about its function or its interacting partners. An important step in converting primary knowledge of genome-scale information to understanding the mechanisms of ART-R is the elucidation of the interactions among the component parts of the biological system. Knowledge of these components can guide appropriate interventions to prolong this crucial drug. We outline a novel approach that is robust to 2 main limitations of genome-wide data: false positives and incomplete information. We validate our approach with the gold standard knowledge that pfcrt is the primary determinant of chloroquine (CQ) resistance and demonstrate its utility for dissecting ART-R. After constructing a comprehensive reference transcriptional network, we generated 2 novel and independent query lists: i) genes that are 'rewired', i.e. diverge dramatically in their co- expression relationships, between CQR and CQS parasites and ii) genes interrupted by piggyBac (pB) insertions that exhibit altered drug susceptibility. For each of these richly informative input gene sets, we used the reference network to find nodes that complete a short path connection among many of these genes. The immediate goal of this application is to apply this approach to the urgent and vexing problem of emerging ART- R, by expanding the reference network and determining the top rewired genes using an extraordinary panel of clinical isolates from the Thailand-Myanmar border (Aim 1) and by screening 128 pB mutants and transfected lines for shifts in ART susceptibility and transcriptional response profiles (Aim 2). This information will be used to independently validate candidate genes and predict functional interactions (Aim 3).

 描述（由适用提供）：疟疾寄生虫，恶性疟原虫继续以惊人的速度杀死人。解决对基于青蒿素（ART）的组合疗法的抗拒挑战将采用全套传统和创新的新工具。令人兴奋的最近发现指出了13染色体基因中的突变，该基因编码了Kelch螺旋桨域作为新兴艺术抗性（ART-R）的标记，但是对其功能或相互作用的伙伴一无所知。转换基因组规模信息的主要知识以了解ART-R的机制的重要步骤是阐明生物系统组成部分之间的相互作用。这些成分的知识可以指导适当的干预措施以延长这种关键药物。我们概述了一种新颖的方法，该方法对全基因组数据的2个主要局限性很强：误报和不完整的信息。我们以黄金标准知识来验证我们的方法，即PFCRT是氯喹（CQ）耐药性的主要决定剂，并证明了其解剖ART-R的实用性。在构建了一个全面的参考转录网络之后，我们生成了2个新颖和独立的查询列表：i）“重新连接”的基因，即在其共表达关系中，CQR和CQS寄生虫之间的差异很大，CQR和CQS寄生虫和II）基因被PiggyBac（Pb）插入，这些插入耗尽了药物敏感性。对于这些丰富的输入基因集，我们使用参考网络来找到这些节点，这些节点可以在许多这些基因之间完成短路连接。该应用程序的直接目的是通过扩展参考网络并使用非凡的临床隔离板来确定最高的ART ART-R的紧急和烦人问题，并确定最高的基因（AIM 1）（AIM 1）（AIM 1）和通过筛选128个PB突变体和筛选艺术敏感性和转换响应率（AIM 2）（目标）2）（目标2）。该信息将用于独立验证候选基因并预测功能相互作用（AIM 3）。

项目成果

An integrative analysis of small molecule transcriptional responses in the human malaria parasite Plasmodium falciparum.

人类疟疾寄生虫恶性疟原虫中小分子转录反应的综合分析。

• DOI: 10.1186/s12864-015-2165-1
• 发表时间: 2015
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Siwo,GeoffreyH;Smith,RogerS;Tan,Asako;Button-Simons,KatrinaA;Checkley,LisaA;Ferdig,MichaelT
• 通讯作者: Ferdig,MichaelT