Regulation mechanisms of Trypanosoma brucei axonemal dynein
布氏锥虫轴丝动力蛋白的调控机制
基本信息
- 批准号:10494466
- 负责人:
- 金额:$ 26.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-15 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:ATP phosphohydrolaseAffectAfrican TrypanosomiasisBacterial InfectionsBehaviorBiochemicalBiochemistryBiologicalBiological AssayBiophysicsCRISPR/Cas technologyCell divisionCellsCenters of Research ExcellenceChagas DiseaseChemicalsChronicCiliaCloningDataDevelopmentDiseaseDrug TargetingDrug resistanceDynein ATPaseElementsEnzymesEukaryotaExhibitsFlagellaFluorescence MicroscopyFrequenciesGenomicsGoalsIn VitroLeadLeishmaniasisLife Cycle StagesLightMalignant NeoplasmsMeasuresMicrotubulesModelingModificationMolecularMolecular MotorsMorphogenesisMotorMovementOutcomeParasitesPathogenicityPersonsPhenotypePost-Translational Protein ProcessingProcessPropertyProteinsProteomicsRegulationResearchStructureTestingTissuesTotal Internal Reflection FluorescentTrypanosomaTrypanosoma brucei bruceiTrypanosomiasisTubulinVirulencearmbasebiophysical modelbiophysical propertiescell motilityforce feedbackinnovationinsightlaser tweezermechanical signalneglected tropical diseasesnoveloptical trapspathogenprogramsreconstitutionsingle moleculetherapeutic targettranscriptome sequencingtransmission processvector
项目摘要
Project Summary/Abstract
Motility is critical to the life cycle and pathogenicity of many parasites. While targeting motility is successful in
the treatment of multiple bacterial diseases, the motility and motile structures of eukaryotic pathogens remain
understudied and underexploited as treatment targets. Kinetoplastids, which are eukaryotic parasites that cause
multiple neglected tropical diseases, exhibit unique flagellar motility. Their flagella beat with a bending wave that
propagates from the tip to the base of their flagellum. This is unlike nearly all other eukaryotes, which beat from
the base to the tip. Because kinetoplastid flagellum bending wave propagation direction switches under certain
chemical and environmental conditions, and because the motile elements of kinetoplastid the flagellum are
nearly identical to all other eukaryotes, it is likely that unique regulation mechanisms innate to axonemal dyneins,
the molecular motors that drive flagellar motility, tune this tip-to-base motility. Testing this hypothesis requires
quantitative single-molecule biophysical characterization of kinetoplastid dynein regulation mechanisms.
The broad goal of this research program is to enable the development of novel treatments for kinetoplastid-
associated diseases that target the tip-to-base motility of kinetoplastid flagella. The specific aims of this project
focus on quantifying axonemal dynein regulation mechanisms from Trypanosoma brucei brucei, which will be
used as a model for kinetoplastid flagella. The aims include characterizing how force regulates the motility of
inner arm axonemal dyneins and how dynein-associated light chains and posttranslational modification to tubulin
regulate outer arm axonemal dyneins. This interdisciplinary project will take molecular biological (CRISPR/Cas9,
cloning, protein tagging), biochemical (in vitro reconstitutions, ATPase assays), genomic and proteomic (RNA-
Seq, mass spec), and biophysical (ultrafast dual-trap optical tweezers, total internal reflectance fluorescence
microscopy) experimental approaches. The collected data will be integrated and understood by making
quantitative biophysical models of axonemal dynein motility mechanisms. The expected outcome will be a
framework from which to develop pan-kinetoplastid drugs that target parasite motility. Successful completion of
the project will ultimately lead to a greater understanding of the fundamental mechanisms of pathogenic parasite
motility and could lead to novel treatments for African sleeping sickness, Chagas disease, and leishmaniasis.
项目总结/文摘
项目成果
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