Discovery of chemically validated malaria liver stage targets
Discovery of chemically validated malaria liver stage targets
批准号:
9056361
负责人:
Elizabeth A Winzeler
金额:
$46.81万
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
已结题
起止时间:
2011-05-06 至 2020-07-31
关键词:
Acetyl Coenzyme AAffectAllelesAnabolismAnimal ModelAntimalarialsArtemisininsBiochemistryBiological AssayBloodCRISPR/Cas technologyChemicalsClinicalClinical TrialsCulicidaeDevelopmentDoseDrug KineticsDrug resistanceEvolutionFormulationFundingGene ExpressionGenesGenome ScanGenomicsGoalsGrowth and Development functionHepatocyteHumanHuman VolunteersIn VitroInfectionIntegral Membrane ProteinInvestigationLaboratoriesLeadLicensingLiverMalariaManuscriptsMembraneMetabolicMetabolic PathwayMethodsMicroscopyMidgutMolecular WeightMusMutationOocystsParasite resistanceParasitesPathway interactionsPatientsPlasmodiumPlasmodium falciparumPlasmodium vivaxPreparationPrimaquinePropertyProphylactic treatmentResistanceRunningSaccharomyces cerevisiaeSafetySeriesSporozoitesStagingSuppressor MutationsSystemTestingUDP-galactose transporterWorkartemisinineasexualbasecyclic aminedesigndigitaldrug candidatedrug developmentdrug discoverydrug efficacyfeedinggenome sequencinggenome-wideimprovedinsightmalaria transmissionmembermetabolomicsnanomolarnovelphase II trialpreventpublic health relevanceresearch studyresistance alleleresistance generesistance mutationresponsescaffoldscreeningshikimatesmall moleculetherapy developmenttranscriptomicstreatment responsewhole genome
中文摘要
英文摘要
DESCRIPTION (provided by applicant): Imidazolopiperazines (IZPs) are a novel class of antimalarial drug in clinical development for the treatment of uncomplicated malaria and malaria prophylaxis. IZPs eliminate blood stage infections and both prevent asymptomatic malaria development and malaria transmission in animal models of malaria. One member of the class has been tested in early clinical trials and is well-tolerated by humans when administered orally. Although parasite resistance to IZPs is conferred by mutations in the Plasmodium falciparum gene encoding the parasite P. falciparum cyclic amine resistance locus (PfCARL), the mechanism of action of the IZP's is not well understood. Further studies on how the IZPs work are therefore needed, We propose to use a suite of genomic methods including metabolomics, transcriptomics and other genome-wide methods to study how IZPs act against all Plasmodium lifecycle forms that parasitize humans, with the goal of identifying their precise target. Specifically, we will first use metabolomics profiling to examine how parasite metabolic pathways respond to parasite IZP treatment in blood stages. We will then compare these metabolic responses to the IZPs to the transcriptional response to IZP treatment in blood stages, liver stages and gametocytes. We will also perform similar analyses against compounds with known mechanisms of action, in order to identify IZP specific effects. Second, we will probe for any additional targets using a well-established experimental pipeline of in vitro evolution followed by whole genome sequencing. Genes with identified resistance mutations will be associated with the pathways identified by metabolomic and transcriptional profiling to identify putative targets. Finally, we will confirm any putative targets in P. falciparum through a series o functional studies.
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Discovery of long-acting, chemoprotective antimalarial compounds
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批准号:10580781
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项目类别:
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资助金额:$69.33万
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财政年份:2020
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负责人:Elizabeth A Winzeler
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依托单位:
Discovery of long-acting, chemoprotective antimalarial compounds
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批准号:10356133
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资助金额:$69.94万
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财政年份:2020
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Discovery of long-acting, chemoprotective antimalarial compounds
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批准号:10132240
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资助金额:$71.26万
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财政年份:2020
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批准号:8892056
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资助金额:$65.23万
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财政年份:2013
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负责人:Elizabeth A Winzeler
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依托单位:
Defining the targets of broad intervention antimalarial agents
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批准号:9109547
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项目类别:
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资助金额:$63.65万
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财政年份:2013
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负责人:Elizabeth A Winzeler
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依托单位:
Defining the targets of broad intervention antimalarial agents
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批准号:8581051
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项目类别:
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资助金额:$64.81万
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财政年份:2013
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负责人:Elizabeth A Winzeler
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依托单位:
Discovery of chemically validated malaria liver stage targets
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批准号:8646859
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项目类别:
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资助金额:$38.75万
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财政年份:2011
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负责人:Elizabeth A Winzeler
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依托单位:
Discovery of chemically validated malaria liver stage targets
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批准号:8263021
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项目类别:
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资助金额:$38.73万
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财政年份:2011
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负责人:Elizabeth A Winzeler
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依托单位:
Discovery of chemically validated malaria liver stage targets
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批准号:8204290
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项目类别:
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资助金额:$47.38万
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财政年份:2011
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负责人:Elizabeth A Winzeler
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依托单位:
Discovery of chemically validated malaria liver stage targets
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批准号:8477121
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项目类别:
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资助金额:$36.43万
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财政年份:2011
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负责人:Elizabeth A Winzeler
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依托单位:
Functional genomic tools for in vivo study of P. vivax
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批准号:7991270
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项目类别:
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资助金额:$23.74万
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财政年份:2010
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负责人:Elizabeth A Winzeler
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依托单位:
PROJECT 4: ENVIRONMENT-GENOME INTERACTIONS
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批准号:9127265
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项目类别:
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资助金额:$49.15万
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财政年份:2010
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负责人:Elizabeth A Winzeler
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依托单位:
PROJECT 4: ENVIRONMENT-GENOME INTERACTIONS
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批准号:9293328
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项目类别:
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资助金额:$28.53万
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财政年份:2010
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负责人:Elizabeth A Winzeler
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依托单位:
PROJECT 4: ENVIRONMENT-GENOME INTERACTIONS
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批准号:8957394
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项目类别:
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资助金额:$48.66万
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财政年份:2010
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负责人:Elizabeth A Winzeler
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依托单位:
PROJECT 4: ENVIRONMENT-GENOME INTERACTIONS
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批准号:9520173
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项目类别:
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资助金额:$28.83万
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财政年份:2010
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负责人:Elizabeth A Winzeler
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依托单位:
Experimental Annotation of the P. Falciparum Genome
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批准号:6973367
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项目类别:
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资助金额:$39.5万
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财政年份:2005
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负责人:Elizabeth A Winzeler
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依托单位:
Experimental Annotation of the P. Falciparum Genome
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批准号:7071834
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项目类别:
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资助金额:$45.38万
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财政年份:2005
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负责人:Elizabeth A Winzeler
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依托单位:
Experimental Annotation of the P. Falciparum Genome
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批准号:7628024
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项目类别:
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资助金额:$44.07万
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财政年份:2005
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负责人:Elizabeth A Winzeler
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依托单位:
Experimental Annotation of the P. Falciparum Genome
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批准号:7214622
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项目类别:
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资助金额:$44.07万
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财政年份:2005
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负责人:Elizabeth A Winzeler
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依托单位:
Experimental Annotation of the P. Falciparum Genome
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批准号:7417477
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项目类别:
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资助金额:$43.23万
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财政年份:2005
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负责人:Elizabeth A Winzeler
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依托单位:
海外基金