Regulation of mitochondrial morphodynamics in Toxoplasma gondii
弓形虫线粒体形态动力学的调控
基本信息
- 批准号:9896491
- 负责人:
- 金额:$ 39.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-03-03 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAmino AcidsApicalApicomplexaAutomobile DrivingAuxinsBiochemistryBiological AssayBiologyBiotinylationCalciumCellsCessation of lifeCo-ImmunoprecipitationsComplexCouplingCytokinesisDevelopmentDiseaseDrug TargetingEconomic BurdenEnvironmentHomeostasisImageImmunocompromised HostIn VitroIndividualKnock-outLassoLeadLifeLife Cycle StagesLightLipidsLytic PhaseMapsMechanicsMediatingMembraneMicroscopyMitochondriaMolecularMolecular GeneticsMonitorMorphologyMutation AnalysisOrganellesParasitesPharmaceutical PreparationsPhenotypePhosphorylation SitePhysiologyPlasmodium falciparumPlayPopulationPositioning AttributePost-Translational Protein ProcessingProcessProteinsProteomicsRegulationResearchResistanceRoleShapesSiteSocietiesStretchingStructureSystemToxoplasmaToxoplasma gondiiToxoplasmosisTransmembrane DomainTubular formationYeastsbasecombatdaughter cellexperimental studyextracellularhealth economicshuman pathogenin vivomutantnovelnovel therapeuticspathogenprotein complexsegregationtissue cultureyeast two hybrid system
项目摘要
A unique feature of parasites of the phylum Apicomplexa, such as Toxoplasma gondii, is the presence of a
single tubular mitochondrion, which is essential for parasite survival and a validated drug target. Most studies
of the apicomplexan mitochondrion have focused on its biochemistry and physiology. By contrast little is known
about the machinery that controls mitochondrial division and that regulate its structure, information that would
be critical for a thorough exploration of the mitochondrion as a drug target. Toxoplasma's singular
mitochondrion is very dynamic and undergoes morphological changes throughout the parasite's life cycle
including during the transition from the intracellular to the extracellular environment. While inside a host cell the
mitochondrion is maintained in a lasso shape that stretches around the parasite periphery where it has regions
of coupling with the parasite pellicle, suggesting the presence of membrane contact sites. Promptly after exit
from the host cell, these contact sites disappear, and the mitochondrion collapses indicating that dynamic
membrane contact sites regulate the positioning of the mitochondrion. Neither the functional significance nor
the proteins needed for the contact between Toxoplasma's mitochondrion and pellicle are known. We have
discovered a novel protein, Fip1, that associates with the mitochondrion and that when knocked out the normal
morphology of the mitochondrion is severely affected. In intracellular fip1 knockout parasites the mitochondrion
is not in a lasso shape as seen in wildtype parasites, but instead it is collapsed. Additionally, proper
mitochondrial segregation is disrupted in the knockout parasites, resulting in parasites with no mitochondrion
and mitochondrial material outside of the parasites. These gross morphological changes are associated with a
significant reduction of parasite propagation and can be rescued by reintroduction of a wildtype copy of Fip1.
Accordingly, we hypothesize that Fip1 mediates contact between the mitochondrion and the parasite pellicle in
a regulatable fashion, and that the Fip1 dependent mitochondrial morphology and dynamics are critical for
parasite propagation. Through a combination of molecular genetics, microscopy and proteomics we will
address the functional relevance and the mechanics of the mitochondrial morphology. In aim one we will
conduct a thorough in vivo and in vitro phenotypic characterization of Fip1 mutant strains to determine the role
of Fip1 and mitochondrial shape in parasite viability. Aim two focuses on identifying and characterizing
components of the Fip1 complex that mediates the association of the mitochondrion with the periphery of the
parasites. Finally, in aim three we will determine the regulatory mechanisms that drive the mitochondrial
morphological changes as the parasite exits its host cell. In conjunction, these experiments will shed light onto
the molecular mechanisms driving and regulating the morphodynamics of the Toxoplasma mitochondrion. As
the mitochondrion of this important human pathogen is essential for its survival and a validated drug target, our
studies will uncover novel targets for the development on new therapeutics.
顶复合体门的寄生虫,如刚地弓形虫,有一个独特的特征
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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Gustavo A Arrizabalaga其他文献
Gustavo A Arrizabalaga的其他文献
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{{ truncateString('Gustavo A Arrizabalaga', 18)}}的其他基金
IMSD at Indiana University School of Medicine through Inclusive Biomedical Research Training Program
印第安纳大学医学院的 IMSD 通过包容性生物医学研究培训计划
- 批准号:
10571029 - 财政年份:2023
- 资助金额:
$ 39.28万 - 项目类别:
Homologs of brassinosteroid signaling proteins in Toxoplasma gondii regulate parasite division
弓形虫中油菜素类固醇信号蛋白的同源物调节寄生虫分裂
- 批准号:
10312866 - 财政年份:2021
- 资助金额:
$ 39.28万 - 项目类别:
Homologs of brassinosteroid signaling proteins in Toxoplasma gondii regulate parasite division
弓形虫中油菜素类固醇信号蛋白的同源物调节寄生虫分裂
- 批准号:
10448293 - 财政年份:2021
- 资助金额:
$ 39.28万 - 项目类别:
Regulation of mitochondrial morphodynamics in Toxoplasma gondii
弓形虫线粒体形态动力学的调控
- 批准号:
10365998 - 财政年份:2020
- 资助金额:
$ 39.28万 - 项目类别:
Interleukin-1 and Steroid Signaling Drive Toxoplasma-induced Prostatic Hyperplasia
Interleukin-1 和类固醇信号传导驱动弓形虫诱发的前列腺增生
- 批准号:
10579258 - 财政年份:2020
- 资助金额:
$ 39.28万 - 项目类别:
Interleukin-1 and Steroid Signaling Drive Toxoplasma-induced Prostatic Hyperplasia
Interleukin-1 和类固醇信号传导驱动弓形虫诱发的前列腺增生
- 批准号:
10159890 - 财政年份:2020
- 资助金额:
$ 39.28万 - 项目类别:
Interleukin-1 and Steroid Signaling Drive Toxoplasma-induced Prostatic Hyperplasia
Interleukin-1 和类固醇信号传导驱动弓形虫诱发的前列腺增生
- 批准号:
10352452 - 财政年份:2020
- 资助金额:
$ 39.28万 - 项目类别:
Regulation of mitochondrial morphodynamics in Toxoplasma gondii
弓形虫线粒体形态动力学的调控
- 批准号:
10580777 - 财政年份:2020
- 资助金额:
$ 39.28万 - 项目类别:
Dissecting the calcium dependent phosphorylation network of Toxoplasma gondii
剖析弓形虫的钙依赖性磷酸化网络
- 批准号:
9085774 - 财政年份:2016
- 资助金额:
$ 39.28万 - 项目类别:
Calcium signaling in the parasitophorous vacuole of Toxoplasma gondii
弓形虫寄生液泡中的钙信号传导
- 批准号:
8948686 - 财政年份:2015
- 资助金额:
$ 39.28万 - 项目类别:
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