A multifactorial pipeline to dissect combinatorial drug efficacy in Tuberculosis
A multifactorial pipeline to dissect combinatorial drug efficacy in Tuberculosis
批准号:
10117593
负责人:
DAVID R SHERMAN
金额:
$73.08万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-08-09 至 2025-07-31
关键词:
AddressAffectAlgorithmsAntibioticsAntitubercular AgentsClinicalCommunicable DiseasesComputational BiologyDataDevelopmentDiseaseDrug CombinationsDrug InteractionsDrug SynergismDrug resistance in tuberculosisEnvironmentGenerationsGenesGeneticGoalsGrowthHumanHypoxiaIn VitroIndividualInfectionIntuitionKnowledgeLifeLinkMalignant NeoplasmsMeasurementMeasuresModelingMolecularMulti-Drug ResistanceMultidrug-Resistant TuberculosisMusMycobacterium tuberculosisNutrientOutcomePharmaceutical PreparationsPharmacotherapyPredispositionProcessPublic HealthRegimenResistanceRiskSpeedStressTestingTherapeuticTuberculosisWorkclinically relevantcombatcombinatorialcostdesigndrug efficacyexperimental studygenetic signatureglobal healthimprovedin silicoin vivomachine learning algorithmmouse modelnew combination therapiesnovel drug combinationnovel therapeuticspandemic diseasepre-clinicalpreclinical developmentpredictive modelingprogramsrelapse patientsresponsesynergismtooltranscriptometranscriptomicstuberculosis drugs
中文摘要
摘要
多药耐药性的迅速蔓延,对新的联合用药产生了巨大的需求
治疗各种疾病的疗法,包括传染病和癌症。在一个
一个紧迫的例子是,耐多药结核病(TB)每年影响约50万人
迫切需要新的药物治疗方案。然而,确定新的治疗方案一直是
部分原因是无法在大量可能的药物中确定优先顺序,
组合。为了满足这一需求,我们已经产生了一个实验接地,机器
学习算法INDIGO-MTB,预测结核药物的协同作用或拮抗作用
组合精度高。在这里,我们建议将INDIGO-MTB调整为多因素
这是一个分析组合药物疗效和推动结核病临床前治疗方案开发的管道。
我们将建立并验证在压力环境下预测药物相互作用的能力。
模拟结核病感染的条件,并提取药物相互作用的分子机制。我们
然后将结合联合收割机协同作用和疗效测量,以创建新的方案排名,
我们将在体外和结核病感染的小鼠模型中进行验证。总之,我们的工作将
建立快速评估结核病药物组合的工具和应用框架
其他需要新的多药疗法的疾病。
英文摘要
ABSTRACT
The rapid spread of multi-drug resistance has created a great need for new combination
therapies to treat a variety of conditions, including infectious diseases and cancer. In one
pressing example, multidrug resistant tuberculosis (TB) affects about 500,000 people each year
and novel drug regimens are sorely needed. However, identifying new regimens has been
daunting in part due to the inability to prioritize among a very large number of possible drug
combinations. To address this need, we have generated an experimentally grounded, machine
learning algorithm, INDIGO-MTB, which predicts the synergy or antagonism of TB drug
combinations with high accuracy. Here we propose to adapt INDIGO-MTB into a multifactorial
pipeline to dissect combinatorial drug efficacy and drive preclinical regimen development for TB.
We will build in and validate the ability to predict drug interactions under stressful environmental
conditions that mimic TB infection, and extract molecular mechanisms of drug interactions. We
will then combine synergy and efficacy measurements to create new regimen rankings, which
we will validate both in vitro and in a mouse model of TB infection. Altogether, our work will
establish a tool for rapid assessment of TB drug combinations and a framework for applying this
approach to other conditions where new multidrug therapies are needed.
期刊论文(0)
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会议论文
Drug tolerance, bacterial heterogeneity and adverse TB treatment outcomes
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批准号:10665037
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项目类别:
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资助金额:$13.32万
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财政年份:2021
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负责人:DAVID R SHERMAN
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依托单位:
Drug tolerance, bacterial heterogeneity and adverse TB treatment outcomes
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批准号:10493290
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项目类别:
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资助金额:$14.37万
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财政年份:2021
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负责人:DAVID R SHERMAN
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依托单位:
A multifactorial pipeline to dissect combinatorial drug efficacy in Tuberculosis
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批准号:10669196
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项目类别:
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资助金额:$72.12万
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财政年份:2021
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负责人:DAVID R SHERMAN
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依托单位:
A multifactorial pipeline to dissect combinatorial drug efficacy in Tuberculosis
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批准号:10465068
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项目类别:
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资助金额:$70.51万
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财政年份:2021
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负责人:DAVID R SHERMAN
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依托单位:
Drug tolerance, bacterial heterogeneity and adverse TB treatment outcomes
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批准号:10271651
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项目类别:
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资助金额:$56.87万
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财政年份:2021
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负责人:DAVID R SHERMAN
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依托单位:
Drug tolerance, bacterial heterogeneity and adverse TB treatment outcomes
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批准号:10907961
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项目类别:
-
资助金额:$33.99万
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财政年份:2021
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负责人:DAVID R SHERMAN
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依托单位:
Project 2: Response to Treatment
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批准号:10339374
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项目类别:
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资助金额:$74.61万
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财政年份:2018
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负责人:DAVID R SHERMAN
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依托单位:
Parallel Microscopic Determination of Fitness (PMDF) to Assess Growth and Viability of Mycobacterium tuberculosis
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批准号:9089849
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项目类别:
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资助金额:$23.63万
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财政年份:2015
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负责人:DAVID R SHERMAN
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依托单位:
Bacterial Determinants of TB Progression
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批准号:8577274
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项目类别:
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资助金额:$58.47万
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财政年份:2013
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负责人:DAVID R SHERMAN
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依托单位:
Data Management and Resource Dissemination Core
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批准号:8577291
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项目类别:
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资助金额:$17.88万
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财政年份:2013
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负责人:DAVID R SHERMAN
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依托单位:
2013 Tuberculosis Drug Development GRC
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批准号:8520841
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项目类别:
-
资助金额:$0.8万
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财政年份:2013
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负责人:DAVID R SHERMAN
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依托单位:
2011 Gordon Research Conference on Tuberculosis Drug Development
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批准号:8125495
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项目类别:
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资助金额:$0.8万
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财政年份:2011
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负责人:DAVID R SHERMAN
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依托单位:
A Novel Clock to Monitor M. tuberculosis in vivo
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批准号:7844978
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项目类别:
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资助金额:$24.1万
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财政年份:2009
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负责人:DAVID R SHERMAN
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依托单位:
A Novel Clock to Monitor M. tuberculosis in vivo
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批准号:7574365
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项目类别:
-
资助金额:$26.47万
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财政年份:2009
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负责人:DAVID R SHERMAN
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依托单位:
Hypoxia, Latency and Reactivation in M.tuberculosis
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批准号:7016314
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项目类别:
-
资助金额:$32.87万
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财政年份:2002
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负责人:DAVID R SHERMAN
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依托单位:
Hypoxia, Latency and Reactivation in M.tuberculosis
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批准号:6655602
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项目类别:
-
资助金额:$34.88万
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财政年份:2002
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负责人:DAVID R SHERMAN
-
依托单位:
Hypoxia, Latency and Reactivation in M.tuberculosis
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批准号:6857094
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项目类别:
-
资助金额:$33.68万
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财政年份:2002
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负责人:DAVID R SHERMAN
-
依托单位:
Hypoxia, Latency and Reactivation in M.tuberculosis
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批准号:6450621
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项目类别:
-
资助金额:$16.66万
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财政年份:2002
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负责人:DAVID R SHERMAN
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依托单位:
Hypoxia, Latency and Reactivation in M.tuberculosis
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批准号:6725521
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项目类别:
-
资助金额:$35.1万
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财政年份:2002
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负责人:DAVID R SHERMAN
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依托单位:
Hypoxia, Latency and Reactivation in M tuberculosis
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批准号:6346504
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项目类别:
-
资助金额:$32.15万
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财政年份:2001
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负责人:DAVID R SHERMAN
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依托单位:
海外基金