Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB
耐多药-广泛耐药结核病新突变的进化和功能意义
基本信息
- 批准号:8704446
- 负责人:
- 金额:$ 70.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-19 至 2017-06-30
- 项目状态:已结题
- 来源:
- 关键词:AmikacinAntibiotic TherapyBacillus (bacterium)BiochemicalBioinformaticsCandidate Disease GeneCapromycinCessation of lifeClassificationCodeCollectionComputer SimulationCountryDatabasesDevelopmentDiagnosticDiagnostic testsDrug Resistant TuberculosisDrug TargetingDrug resistanceDrug resistance in tuberculosisEpidemicEtiologyEvolutionExtreme drug resistant tuberculosisFluoroquinolonesFundingFutureGene MutationGene ProteinsGenesGenetic MarkersGenomeGoalsIndiaInjectableKanamycinLaboratoriesLeadLesionLightLocationLungMicrobeModelingMoldovaMoxifloxacinMulti-Drug ResistanceMutationMycobacterium tuberculosisPatientsPharmaceutical PreparationsPhilippinesPhylogenetic AnalysisPhylogenyProteinsPublic HealthPublishingRecombinantsRegulatory ElementReportingResistanceResourcesRifampinRoleRouteSequence AlignmentSiteSouth AfricaTechnologyTreatment FailureWorkbacterial resistancebasedeep sequencingfallsgene interactionimprovedisoniazidmutantnovelprotein protein interactionpublic health relevanceresistance mechanismresistance mutationtrendtuberculosis drugstuberculosis treatment
项目摘要
DESCRIPTION (provided by applicant): Last year over 9 million cases of active TB and 1 million deaths due to TB were reported. The development of drug-resistant Mtb is increasing and threatens TB control efforts. Global Consortium for Drug-resistant TB and Diagnostics (GCDD) has identified over 100 (out of 419) resistant Mtb isolates without known resistance-causing mutations. Additionally, GCDD has identified distinct regional genotypic-phenotypic relationships at its four study sites (India, Moldova, the Philippines, and South Africa) for seven
first and second line drugs, suggesting that Mtb is taking a different evolutionary route to resistance at each site. This could also mean that Mtb is using different mechanisms for producing resistance at these study sites and therefore could soon require new set of anti-TB drugs for each evolutionary path/study site. While the emergence of the distinct evolutionary paths are probably due to variable availability of anti-TB drugs, the emergence of this distinctiveness is alarming and if continued, Mtb can evolve into different states of total drug resistance (TDR- TB) causing an epidemic that requires region-specific treatment and public health strategy. This project aims to uncover previously-unknown mechanisms of drug resistance through in silico functional characterization of newly identified gene and regulatory elements associated with drug resistance. This will explain the unexplained cases of resistance. The functional characterization will allow the identification of the mechanism of resistance for each drug involving these novel mutations, identification of "keystone" mutations that can cause resistance to multiple drugs, and identify central loci in the functional interaction network that can serve as new drug targets. This project will also perform a phylogenetic analysis of all 400+ GCDD Mtb genomes. The combination of functional characterization of novel and known mutations and the evolutionary analysis of drug resistance will answer whether distinct evolutionary paths and mechanisms of resistance are a reality or not. If so, the model can be extended to predict future regional evolutionary trends. Experimental recombinant technology will be used to confirm the significant the keystone mutations responsible for resistance in the laboratory.
描述(由申请人提供):去年报告了超过 900 万例活动性结核病病例和 100 万人因结核病死亡。耐药结核分枝杆菌的发展正在增加,威胁着结核病控制工作。全球耐药结核病和诊断联盟 (GCDD) 已鉴定出超过 100 种(共 419 种)耐药结核分枝杆菌分离株,且没有已知的引起耐药性的突变。此外,GCDD 在其四个研究地点(印度、摩尔多瓦、菲律宾和南非)确定了七个不同区域的基因型-表型关系
一线和二线药物,表明结核分枝杆菌在每个位点采取不同的耐药进化路线。这也可能意味着结核分枝杆菌在这些研究地点使用不同的机制产生耐药性,因此可能很快就需要为每个进化路径/研究地点提供一套新的抗结核药物。虽然不同进化路径的出现可能是由于抗结核药物的可用性存在差异,但这种独特性的出现令人震惊,如果持续下去,结核分枝杆菌可能会演变成不同的完全耐药状态(TDR-TB),从而导致流行病需要针对特定地区的治疗和公共卫生策略。该项目旨在通过对新发现的基因和与耐药性相关的调控元件进行计算机功能表征,揭示以前未知的耐药机制。这将解释无法解释的抵抗情况。功能表征将允许识别涉及这些新突变的每种药物的耐药机制,识别可导致多种药物耐药的“关键”突变,并识别功能相互作用网络中可作为新药物靶点的中心位点。该项目还将对所有 400 多个 GCDD Mtb 基因组进行系统发育分析。新颖和已知突变的功能表征与耐药性的进化分析相结合,将回答不同的进化路径和耐药机制是否真实存在。如果是这样,该模型可以扩展以预测未来的区域演化趋势。实验重组技术将用于在实验室中确认导致耐药性的关键突变的显着性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Faramarz Valafar其他文献
Faramarz Valafar的其他文献
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{{ truncateString('Faramarz Valafar', 18)}}的其他基金
Undetected Drug resistance and Tolerance in lesions of recurrent TB
复发性结核病灶中未检测到的耐药性和耐受性
- 批准号:
10454640 - 财政年份:2022
- 资助金额:
$ 70.41万 - 项目类别:
Undetected Drug resistance and Tolerance in lesions of recurrent TB
复发性结核病灶中未检测到的耐药性和耐受性
- 批准号:
10656341 - 财政年份:2022
- 资助金额:
$ 70.41万 - 项目类别:
Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB
耐多药-广泛耐药结核病新突变的进化和功能意义
- 批准号:
8596784 - 财政年份:2013
- 资助金额:
$ 70.41万 - 项目类别:
Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB
耐多药-广泛耐药结核病新突变的进化和功能意义
- 批准号:
9980263 - 财政年份:2013
- 资助金额:
$ 70.41万 - 项目类别:
Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB
耐多药-广泛耐药结核病新突变的进化和功能意义
- 批准号:
9109555 - 财政年份:2013
- 资助金额:
$ 70.41万 - 项目类别:
Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB
耐多药-广泛耐药结核病新突变的进化和功能意义
- 批准号:
10212921 - 财政年份:2013
- 资助金额:
$ 70.41万 - 项目类别:
Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB
耐多药-广泛耐药结核病新突变的进化和功能意义
- 批准号:
10212921 - 财政年份:2013
- 资助金额:
$ 70.41万 - 项目类别:
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Evolutionary and Functional Significance of Novel Mutations in MDR-XDR TB
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