Mitochondrial Function in Bloodstream Trypanosoma brucei

布氏锥虫血流中的线粒体功能

基本信息

  • 批准号:
    8064395
  • 负责人:
  • 金额:
    $ 36.73万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-05-01 至 2012-12-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Trypanosomatids are protozoan pathogens that cause disease in man and livestock. Most drugs are increasingly ineffective due to toxicity and development of resistance. Mitochondrial gene expression and function are essential for survival of the parasite - despite the absence of oxidative phosphorylation in the long slender bloodstream (LS) form - and may represent powerful targets for new drugs. However, mitochondrial biology in the LS stage is poorly understood and the essential function of the organelle for the parasite is not known. This project will test the hypothesis that respiratory complexes I (NADH:ubiquinone oxidoreductase) and/or V (ATP synthase) are required for viability of LS parasites and that essential components of one or both of these complexes are mitochondrially expressed. This hypothesis is based on evidence that these complexes are active in the LS form and on the in silico identification of mitochondrial genes encoding putative subunits of these complexes. (1) Complexes I and V will be inactivated by silencing the expression of essential nuclearly encoded subunits and the effects on cell growth and on parameters of mitochondrial function such as ATP levels, respiration, membrane potential, and protein import will be examined. (2) The hypothesis will be tested that mitochondrial genes encode subunits of respiratory complexes I and V by identifying the interaction partners of the gene products in vivo. Protein purification and identification will be achieved through affinity tagging and mass spectrometry. (3) The requirement for RNA editing and activities identified in (1) will be determined in dyskinetoplastic (dk) trypanosomes, which have lost their mitochondrial DNA and may thus indicate potential routes for drug resistance. (4) Potential compensatory mutations in dk trypanosomes will be identified by cloning and sequencing of key nuclearly encoded subunits. These studies will provide novel insights into mitochondrial function in trypanosomatids, validate new drug targets, and assess the potential for resistance to drugs targeting mitochondrial function. Relevance: Trypanosomatids are unicellular parasites and the causative agents of diseases with devastating health and economic consequences, such as African sleeping sickness and Leishmaniasis. This project will characterize the role of the mitochondrion - a cell organelle - in the disease-causing stage of the parasite. This research will help to identify new drug targets and to understand the action of existing drugs.
描述(由申请人提供):锥虫是引起人类和牲畜疾病的原生动物病原体。由于毒性和耐药性的发展,大多数药物越来越无效。线粒体基因的表达和功能对寄生虫的生存至关重要——尽管在细长的血流(LS)形式中缺乏氧化磷酸化——并且可能代表新药的有力靶点。然而,线粒体生物学在LS阶段是知之甚少和细胞器的寄生虫的基本功能尚不清楚。该项目将测试呼吸复合物I (NADH:泛醌氧化还原酶)和/或V (ATP合成酶)是LS寄生虫生存所必需的假设,并且这些复合物的一种或两种基本成分是线粒体表达的。这一假设是基于这些复合物以LS形式活跃的证据,以及对编码这些复合物的假定亚基的线粒体基因的计算机鉴定。(1)复合物I和V将通过沉默必需核编码亚基的表达而失活,并将检查对细胞生长和线粒体功能参数(如ATP水平、呼吸、膜电位和蛋白质输入)的影响。(2)通过鉴定基因产物在体内的相互作用伙伴,验证线粒体基因编码呼吸复合体I和V亚基的假设。蛋白质的纯化和鉴定将通过亲和标记和质谱来实现。(3)在(1)中鉴定的RNA编辑需求和活性将在失活体(dk)锥虫中确定,这些锥虫已经失去了线粒体DNA,因此可能提示潜在的耐药途径。(4) dk锥虫潜在的代偿性突变将通过对关键核编码亚基的克隆和测序来鉴定。这些研究将为锥虫线粒体功能提供新的见解,验证新的药物靶点,并评估针对线粒体功能的药物的耐药潜力。相关性:锥虫病是单细胞寄生虫,是非洲昏睡病和利什曼病等具有破坏性健康和经济后果的疾病的病原体。该项目将描述线粒体-一种细胞器-在寄生虫致病阶段的作用。这项研究将有助于确定新的药物靶点,并了解现有药物的作用。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Evolution of dyskinetoplastic trypanosomes: how, and how often?
运动障碍锥虫的进化:如何进化以及多久进化一次?
  • DOI:
    10.1016/j.pt.2010.08.001
  • 发表时间:
    2010
  • 期刊:
  • 影响因子:
    9.6
  • 作者:
    Schnaufer,Achim
  • 通讯作者:
    Schnaufer,Achim
NADH dehydrogenase of Trypanosoma brucei is important for efficient acetate production in bloodstream forms.
  • DOI:
    10.1016/j.molbiopara.2016.10.001
  • 发表时间:
    2017-01
  • 期刊:
  • 影响因子:
    1.5
  • 作者:
    Surve SV;Jensen BC;Heestand M;Mazet M;Smith TK;Bringaud F;Parsons M;Schnaufer A
  • 通讯作者:
    Schnaufer A
Genome and phylogenetic analyses of Trypanosoma evansi reveal extensive similarity to T. brucei and multiple independent origins for dyskinetoplasty.
伊氏锥虫的基因组和系统发育分析揭示了与布氏锥虫的广泛相似性以及运动障碍的多个独立起源
  • DOI:
    10.1371/journal.pntd.0003404
  • 发表时间:
    2015-01
  • 期刊:
  • 影响因子:
    3.8
  • 作者:
    Carnes J;Anupama A;Balmer O;Jackson A;Lewis M;Brown R;Cestari I;Desquesnes M;Gendrin C;Hertz-Fowler C;Imamura H;Ivens A;Kořený L;Lai DH;MacLeod A;McDermott SM;Merritt C;Monnerat S;Moon W;Myler P;Phan I;Ramasamy G;Sivam D;Lun ZR;Lukeš J;Stuart K;Schnaufer A
  • 通讯作者:
    Schnaufer A
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Marilyn Parsons其他文献

Marilyn Parsons的其他文献

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{{ truncateString('Marilyn Parsons', 18)}}的其他基金

Functional analysis of an essential Trypanosoma brucei protein kinase
布氏锥虫必需蛋白激酶的功能分析
  • 批准号:
    9316312
  • 财政年份:
    2017
  • 资助金额:
    $ 36.73万
  • 项目类别:
Trypanosome transmembrane kinases
锥虫跨膜激酶
  • 批准号:
    8445189
  • 财政年份:
    2013
  • 资助金额:
    $ 36.73万
  • 项目类别:
Trypanosome transmembrane kinases
锥虫跨膜激酶
  • 批准号:
    8605509
  • 财政年份:
    2013
  • 资助金额:
    $ 36.73万
  • 项目类别:
The Plastid of Toxoplasma gondii
弓形虫质体
  • 批准号:
    8070872
  • 财政年份:
    2010
  • 资助金额:
    $ 36.73万
  • 项目类别:
The Plastid of Toxoplasma gondii
弓形虫质体
  • 批准号:
    7846699
  • 财政年份:
    2009
  • 资助金额:
    $ 36.73万
  • 项目类别:
Mitochondrial Function in Bloodstream Trypanosoma brucei
布氏锥虫血流中的线粒体功能
  • 批准号:
    7617156
  • 财政年份:
    2007
  • 资助金额:
    $ 36.73万
  • 项目类别:
Mitochondrial Function in Bloodstream Trypanosoma brucei
布氏锥虫血流中的线粒体功能
  • 批准号:
    7414452
  • 财政年份:
    2007
  • 资助金额:
    $ 36.73万
  • 项目类别:
Mitochondrial Function in Bloodstream Trypanosoma brucei
布氏锥虫血流中的线粒体功能
  • 批准号:
    7795085
  • 财政年份:
    2007
  • 资助金额:
    $ 36.73万
  • 项目类别:
The Plastid of Toxoplasma gondii
弓形虫质体
  • 批准号:
    7622173
  • 财政年份:
    2002
  • 资助金额:
    $ 36.73万
  • 项目类别:
The Plastid of Toxoplasma gondii
弓形虫质体
  • 批准号:
    7555004
  • 财政年份:
    2002
  • 资助金额:
    $ 36.73万
  • 项目类别:

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