The role of polyphosphate and acidocalcisomes in Trypanosoma brucei
多磷酸盐和酸钙体在布氏锥虫中的作用
基本信息
- 批准号:8084196
- 负责人:
- 金额:$ 36.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAbbreviationsAdverse effectsAffectAfrica South of the SaharaAfrican TrypanosomiasisAgingAnimal Disease ModelsAnimal ModelAnthrax diseaseAntifibrinolytic AgentsAntifungal AgentsApoptosisAzolesBacteriaBenznidazoleBiologyBlood PlateletsCa(2+)-Transporting ATPaseCalciumCationsCattleCellsCessation of lifeChagas DiseaseChemistryChlamydomonas reinhardtiiCoagulantsComplexCytoplasmic GranulesDevelopmentDictyostelium discoideumDiphosphatesDiseaseDysenteryEnergy-Filtering Transmission Electron MicroscopyEnzymesEvolutionFossilsGene ExpressionGeneticGentian VioletGoalsGrantGreen AlgaeGrowth and Development functionHealthHemorrhageHomeostasisHumanIncidenceInfectionInfection ControlIntegral Membrane ProteinKnowledgeLaboratoriesLeadLeishmaniasisMaintenanceMalariaMalignant NeoplasmsMammalian CellMembraneMetabolicMetabolic PathwayMetabolismModelingMolecularMolecular GeneticsMorbidity - disease rateNamesNatureNifurtimoxOrganellesOsmoregulationOsteoporosisParasite ControlParasitesPersonsPharmaceutical PreparationsPhenotypePhosphorusPhysarum polycephalumPhysiologyPlatelet ActivationPlayPolymersPolyphosphate kinasePolyphosphatesProteinsProteomicsProton-Translocating ATPasesProtonsPumpRiskRoleSet proteinSignal TransductionSterile coveringsTestingTextTrypanocidal AgentsTrypanosomaTrypanosoma brucei bruceiTrypanosoma cruziTrypanosomiasisTuberculosisVaccinesVirulenceWorkWorld Health Organizationanalogbisphosphonatecalcium metabolismcareerchemotherapeutic agentchemotherapycomparativedesigninhibitor/antagonistmanmicroorganismmortalitynovelpH Homeostasispreventproton-translocating pyrophosphatasepyrophosphatasetooltraffickingwater channelwound
项目摘要
DESCRIPTION (provided by applicant): Trypanosoma brucei is the causative agent of sleeping sickness or African trypanosomiasis. According to the World Health Organization, over 60 million persons in sub-Saharan Africa are at risk of infection with an incidence of 300-500,000 cases per year resulting in 55,000 deaths. African trypanosomiasis has been reemerging since 1970, and chemotherapy remains unsatisfactory, especially for advanced cases. The acidocalcisome is a dense, acidic organelle with a high concentration of phosphorus present as pyrophosphate and polyphosphate complexed with calcium, and other cations. The acidocalcisome membrane contains a number of pumps (Ca2+- ATPase, V-H+-ATPase, H+-PPase), exchangers (Na+/H+, Ca2+/H+), and channels (aquaporins), while its matrix contains enzymes related to pyrophosphate and polyphosphate metabolism. Acidocalcisomes have been found in several pathogenic microorganisms as well as in the green alga Chlamydomonas reinhardtii, and the slime mold Dictyostelium discoideum. The identification of the acidocalcisome in bacteria and the finding that human platelet dense granules are similar to acidocalcisomes, indicate that this organelle either appeared before the divergence of bacterial and eukaryotic lineages or independently by convergent evolution. Some of the potential functions of the acidocalcisome are the storage of cations and phosphorus, and its participation in pyrophosphate and polyphosphate metabolism, calcium homeostasis, maintenance of intracellular pH homeostasis, and osmoregulation. T. brucei is an excellent model to study the acidocalcisome and our goal is to know its composition and function. In recent years we have demonstrated the presence of novel enzymes in this organelle that are absent from mammalian cells and this led to the finding of compounds (pyrophosphate analogs) that produced radical cures in animal models of diseases caused by several parasites. Further exploration of the composition and function of the acidocalcisome in T. brucei could lead to the identification of new targets for chemotherapeutic agents. We will focus on studying the composition and function of the acidocalcisome proteins of T. brucei, the targeting mechanism of transmembrane proteins to this organelle, and the roles of pyrophosphate and polyphosphate metabolism in T. brucei growth and development. PUBLIC HEALTH RELEVANCE: Our goal is to find ways of interfering with Trypanosoma brucei metabolic pathways as a strategy of controlling infections caused by this and similar parasites. The polyphosphate and acidocalcisome metabolic pathways may be good targets for new trypanocidal agents and this work is designed to test the function and significance of polyphosphate and acidocalcisomes of T. brucei.
描述(由申请人提供):布鲁氏锥虫是昏睡病或非洲锥虫病的病原体。据世界卫生组织称,撒哈拉以南非洲有6 000多万人面临感染风险,每年发病率为300-50万例,造成55 000人死亡。非洲锥虫病自1970年以来再次出现,化疗仍然不令人满意,特别是对晚期病例。酸钙体是一种致密的酸性细胞器,含有高浓度的磷,以焦磷酸盐和多磷酸盐与钙和其他阳离子络合的形式存在。酸钙体膜含有许多泵(Ca2+- ATPase, V-H+-ATPase, H+- ppase),交换剂(Na+/H+, Ca2+/H+)和通道(水通道蛋白),而其基质含有与焦磷酸盐和多磷酸盐代谢相关的酶。在几种致病微生物中以及绿藻莱茵衣藻和黏菌盘基钢菌中都发现了酸钙体。细菌中酸钙体的鉴定和人类血小板致密颗粒与酸钙体相似的发现表明,这种细胞器要么出现在细菌和真核生物谱系分化之前,要么是通过趋同进化独立存在的。酸钙体的一些潜在功能是储存阳离子和磷,参与焦磷酸盐和多磷酸盐代谢,钙稳态,维持细胞内pH稳态和渗透调节。布鲁氏体是研究酸溶酶体的一个很好的模型,我们的目标是了解它的组成和功能。近年来,我们已经证明在这种细胞器中存在哺乳动物细胞中不存在的新酶,这导致了化合物(焦磷酸盐类似物)的发现,这些化合物在动物模型中对几种寄生虫引起的疾病产生了根治。进一步研究布鲁氏菌酸钙酶体的组成和功能,有助于发现化疗药物的新靶点。我们将重点研究布氏体酸溶酶体蛋白的组成和功能,跨膜蛋白对该细胞器的靶向机制,焦磷酸盐和多磷酸盐代谢在布氏体生长发育中的作用。公共卫生相关性:我们的目标是找到干扰布氏锥虫代谢途径的方法,作为控制由该寄生虫和类似寄生虫引起的感染的策略。多磷酸盐和酸钙体代谢途径可能是新型锥虫药物的良好靶点,本研究旨在测试布鲁氏锥虫多磷酸盐和酸钙体的功能和意义。
项目成果
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{{ truncateString('ROBERTO DOCAMPO', 18)}}的其他基金
Polyphosphate and cardiac fibrosis by Trypanosoma cruzi
克氏锥虫的多磷酸盐与心脏纤维化
- 批准号:
10740934 - 财政年份:2023
- 资助金额:
$ 36.39万 - 项目类别:
Piezo channels and calcium signaling in Trypanosoma cruzi
克氏锥虫的压电通道和钙信号传导
- 批准号:
10371132 - 财政年份:2021
- 资助金额:
$ 36.39万 - 项目类别:
Piezo channels and calcium signaling in Trypanosoma cruzi
克氏锥虫的压电通道和钙信号传导
- 批准号:
10216716 - 财政年份:2021
- 资助金额:
$ 36.39万 - 项目类别:
The mitochondrial calcium uniporter of trypanosomes
锥虫线粒体钙单向转运蛋白
- 批准号:
8651736 - 财政年份:2014
- 资助金额:
$ 36.39万 - 项目类别:
The mitochondrial calcium uniporter of trypanosomes
锥虫线粒体钙单向转运蛋白
- 批准号:
8874884 - 财政年份:2014
- 资助金额:
$ 36.39万 - 项目类别:
Global gene expression analysis of Trypanosoma cruzi under hyperosmotic stress
高渗胁迫下克氏锥虫全局基因表达分析
- 批准号:
8010207 - 财政年份:2009
- 资助金额:
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