Elucidating the Role of Endocytosis Via the Cytostome in the Life Cycle of Trypanosoma cruzi
阐明细胞口内吞作用在克氏锥虫生命周期中的作用
基本信息
- 批准号:10414106
- 负责人:
- 金额:$ 47.98万
- 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
- 起止时间:2021-06-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAmericasArthropod VectorsBasic ScienceBiologicalBiologyCRISPR/Cas technologyCell membraneCellsChagas DiseaseClinicalComplexCytosolDataDefectDigestionDiseaseElementsEndocytosisEnvironmentEtiologyFamilyFecesGastrointestinal tract structureGene DeletionGenesGeneticGoalsGrowthHindgutHumanIndividualInfectionIngestionInsect VectorsInsectaInvadedKnock-outLeishmaniaLifeLife Cycle StagesLightLipidsMeasurableMediatingMolecularMolecular AnalysisMolecular MotorsMolecular TargetMotorMyosin ATPaseNutrientOralOrganellesOrganismOrphanParasitesParasitic infectionPathway interactionsPersonsPlayPopulations at RiskProcessProteinsProteomicsPublishingRectumResourcesRoleStructureSuggestionSurfaceTechniquesTechnologyTimeTrypanosoma brucei bruceiTrypanosoma cruziTubular formationValidationVesicleWorkburden of illnesscombatcomparativeelectron tomographyextracellularfeedinggastrointestinalinsightknockout genelipidomicsmutantneglectnovelobligate intracellular parasitepathogenprotein complexsubcellular targetingtooltransmission processuptakevectorvector transmissionvirtual
项目摘要
PROJECT SUMMARY
The etiological agent of Chagas disease, Trypanosoma cruzi, is an obligate intracellular parasite that infects an
estimated 10 million people in the Americas, with an at-risk population of 70 million. Despite its recognition as
the highest impact parasitic infection of the Americas, Chagas disease remains underreported, understudied
and underfunded. Basic research into the biology of T. cruzi has previously been hindered by a lack of efficient
genetic tools, but the advent of CRISPR/Cas9 gene editing technology has cleared the way for more in-depth
molecular analyses. Among the human infecting parasitic trypanosomatids, T. cruzi is extremely unique for a
number of reasons: it develops into its infectious form in the hindgut of insects, is transmitted to its mammalian
host via the feces of its insect vector, lives directly in the cytosol of its mammalian host cell and utilizes an
ancient feeding organelle to endocytose extracellular material in a manner much like its bacterivorous free-
living relatives. This endocytic structure is composed of a long tubular invagination (cytopharynx) starting at a
surface plasma membrane pore (cytostome) which we refer to here as the cytostome/cytopharynx complex or
SPC. The SPC is a highly dynamic organelle that is present and functional only in the replicating forms of the
parasite and disassembles during the transition to its infectious stages. Until recently the SPC had only been
examined using electron tomography techniques and had resisted molecular analysis as the protein
components comprising it remained elusive. Our initial published work described the first proteins known to be
targeted to the SPC and was followed by the identification of a family of SPC targeted myosin motors that we
show contribute directly to the endocytic process. Recently, however, we have identified an essential myosin
regulatory component of the SPC (MyAP1), a knockout of which resulted in parasites that are completely
devoid of measurable endocytosis and who are defective in their ability to scavenge host lipids. Although viable
in culture, we have also demonstrated through infections of the insect vector (R. prolixus) that endocytosis is
critical for the parasite to be able to establish a robust infection and colonize the insect hindgut, a necessary
step for effective transmission to its mammalian host. Completion of this study will allow us to continue to
elucidate the molecular machinery responsible for the formation and function of the SPC as well as give insight
into why it is that T. cruzi retained this ancient mode of nutrient uptake. Our endocytic-null mutant also gives us
the unique opportunity to finally examine the “endocytome” of this parasite. Although not limited to lipids, we
are excited by preliminary data allowing us for the first time to now distinguish which lipids are actively being
scavenged through endocytosis from those which the parasite is able to endogenously produce for itself. The
goal for this proposal is ultimately to give greater insight into parasite pathways essential for vector
transmission as well as provide a window into the biosynthetic pathways that are actively present and
necessary for parasite viability.
项目摘要
Chagas疾病的病因学药Cruzi是一种强制性细胞内寄生虫,感染了
估计在美洲人口有1000万人,高危人口为7000万。尽管它被认为是
恰加斯病在美洲的寄生寄生虫感染最高,据了解
而且资金不足。缺乏有效的效率
遗传工具,但是CRISPR/CAS9基因编辑技术的冒险已经为更深入的方法扫清了道路
分子分析。在人类感染的寄生锥虫中,T。cruzi对于A非常独特
许多原因:它在昆虫的后肠上发展成传染性形式,已传播到其哺乳动物
通过其昆虫载体的粪便宿主直接生活在其哺乳动物宿主细胞的细胞质中,并利用
古老的喂养细胞器以类似于细菌自由的方式向内吞细胞外材料
亲戚。这种内吞结构由长管的内向(细胞咽部)组成
表面质膜孔(细胞体),我们在这里称为细胞抑制剂/细胞咽部复合物或
SPC。 SPC是一种高度动态的细胞器,仅在复制形式中起作用,并且功能
在过渡到传染性阶段的过程中,寄生虫和拆卸。直到最近,SPC才是
使用电子断层扫描技术检查,并抗性分子分析作为蛋白质
完成它的组件仍然难以捉摸。我们最初发表的工作描述了第一种已知的蛋白质
针对SPC的针对性,随后是SPC靶向肌球蛋白电机家族的鉴定
显示直接有助于内吞过程。但是,最近,我们确定了一个必不可少的肌球蛋白
SPC(Myap1)的调节成分,其敲除的寄生虫完全是寄生虫
没有可测量的内吞作用,并且在清除宿主脂质的能力方面缺乏缺陷。虽然可行
在培养中,我们还通过对绝缘载体(R. prolixus)的感染来证明内吞作用是
寄生虫能够建立强大的感染并定居隔热至关重要,这是必要的
有效传输到其哺乳动物宿主的步骤。这项研究的完成将使我们能够继续
阐明负责SPC形成和功能的分子机制,并提供洞察力
为什么T. Cruzi保留了这种古老的养分吸收方式。我们的内吞无效突变体也给了我们
最终检查该寄生虫的“内吞”的独特机会。尽管不限于脂质,但我们
通过初步数据兴奋
通过内吞作用从寄生虫能够自身产生的那些内吞作用中清除。
该提议的目标最终是为了更深入地了解寄生虫途径的寄生虫途径
传输以及提供积极存在的生物合成途径的窗口,
寄生虫生存能力所必需的。
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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RONALD DREW ETHERIDGE其他文献
RONALD DREW ETHERIDGE的其他文献
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{{ truncateString('RONALD DREW ETHERIDGE', 18)}}的其他基金
Elucidating the Mechanistic Basis for Phagotrophy in the Protozoan Trypanosoma cruzi (equipment supplement)
阐明原生动物克氏锥虫吞噬作用的机制基础(设备补充)
- 批准号:
10799091 - 财政年份:2022
- 资助金额:
$ 47.98万 - 项目类别:
Elucidating the Mechanistic Basis for Phagotrophy in the Protozoan Trypansoma cruzi
阐明原生动物克氏锥虫吞噬作用的机制基础
- 批准号:
10345248 - 财政年份:2022
- 资助金额:
$ 47.98万 - 项目类别:
Elucidating the Mechanistic Basis for Phagotrophy in the Protozoan Trypansoma cruzi
阐明原生动物克氏锥虫吞噬作用的机制基础
- 批准号:
10630908 - 财政年份:2022
- 资助金额:
$ 47.98万 - 项目类别:
Elucidating the Role of Endocytosis Via the Cytostome in the Life Cycle of Trypanosoma cruzi
阐明细胞口内吞作用在克氏锥虫生命周期中的作用
- 批准号:
10279960 - 财政年份:2021
- 资助金额:
$ 47.98万 - 项目类别:
Elucidating the Role of Endocytosis Via the Cytostome in the Life Cycle of Trypanosoma cruzi
阐明细胞口内吞作用在克氏锥虫生命周期中的作用
- 批准号:
10626864 - 财政年份:2021
- 资助金额:
$ 47.98万 - 项目类别:
Characterizing the unique endocytic organelle of Trypanosoma cruzi
表征克氏锥虫独特的内吞细胞器
- 批准号:
9808880 - 财政年份:2019
- 资助金额:
$ 47.98万 - 项目类别:
CHARACTERIZATION OF ESSENTIAL RHOPTRY KINASES OF TOXOPLASMA GONDII
弓形虫必需的棒状体激酶的特征
- 批准号:
8202521 - 财政年份:2011
- 资助金额:
$ 47.98万 - 项目类别:
CHARACTERIZATION OF ESSENTIAL RHOPTRY KINASES OF TOXOPLASMA GONDII
弓形虫必需的棒状体激酶的特征
- 批准号:
8504684 - 财政年份:2011
- 资助金额:
$ 47.98万 - 项目类别:
CHARACTERIZATION OF ESSENTIAL RHOPTRY KINASES OF TOXOPLASMA GONDII
弓形虫必需的棒状体激酶的特征
- 批准号:
8490510 - 财政年份:2011
- 资助金额:
$ 47.98万 - 项目类别:
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