MITOPlas_Scalable characterization of the malaria parasite mitochondrial proteome

MITOPlas_疟原虫线粒体蛋白质组的可扩展表征

基本信息

  • 批准号:
    9014806
  • 负责人:
  • 金额:
    $ 23.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-01-01 至 2017-12-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Our ability to effectively treat malaria is threatened by increasingly widespread resistance to the limited number of frontline antimalarial drugs available. Consequently, new strategies guiding prioritization of novel targets for drug development are critically needed. Here we propose targeting mitochondrial function as a strategy that could yield diverse solutions for treating malaria. The long-term goal is to define the mitochondrial proteome of the human malaria parasite, P. falciparum, and establish the core subset of these proteins that are essential for parasite survival. We envision that this knowledge will contribute to the development of new antimalarial drugs with novel mechanisms of action, and that circumvent existing modes of drug resistance. The objectives of the present research are to: (1) develop a pipeline for prioritizing then validating the set of nuclear- encoded protein that are trafficked to the mitochondrion; and (2) classify the essentiality of these proteins. The central hypothesis is that mitochondrial function is critical for malaria parasite survival during blood, mosquito and liver stages. Defining essential mitochondrial proteins and biological processes should provide new insights into fundamental parasite biology. Additionally, this can create opportunities for developing antimalarial drugs that simultaneously target blood, transmission, and liver stages of the parasite life cycle. Drugs with these characteristics are critical to malaria elimination efforts. To accomplish the objectives of this proposal, we will pursue two aims. In Specific Aim 1, we will use bioinformatics tools to predict mitochondrial targeting sequences (MTS) in nuclear-encoded proteins, and create prioritized lists of putative mitochondrial proteins. We will create libraries of MTS candidates fused to a fluorescent reporter protein and use high throughput and high content imaging to determine whether a candidate MTS is sufficient to mediate protein trafficking to the mitochondrion. In Specific Aim 2, we will use a newly developed functional genetics toolkit to epitope tag and conditionally regulate the expression level of endogenous proteins putatively trafficked to the mitochondrion. This will allow us to establish whether native proteins associated with a given MTS are indeed trafficked to the mitochondrion. Conditionally regulating the expression of these proteins will additionally facilitate assessment of which mitochondrial proteins are essential for parasite survival. Our approach is innovative because it integrates several complementary technologies-combinatorial reporter library synthesis and parasite line generation, high content imaging and functional genetics-to gain insight into mitochondrial biology on an unprecedented scale in P. falciparum. The proposed research is significant because it will provide definitive insights into the composition and vital components of this relatively enigmatic parasite organelle. Simultaneously, it will motivate targeted interference with mitochondrial function as a strategy for identifying life cycle stage-independent antimalarial drugs. These outcomes are expected to positively impact human health by improving the tools available for malaria treatment and eradication.


项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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{{ truncateString('JACQUIN C NILES', 18)}}的其他基金

Target-specific antimalarial compound identification using phenotypic assays
使用表型分析鉴定靶标特异性抗疟化合物
  • 批准号:
    10404548
  • 财政年份:
    2019
  • 资助金额:
    $ 23.4万
  • 项目类别:
Target-specific antimalarial compound identification using phenotypic assays
使用表型分析鉴定靶标特异性抗疟化合物
  • 批准号:
    10177856
  • 财政年份:
    2019
  • 资助金额:
    $ 23.4万
  • 项目类别:
Engineered Regulated RNA Localization and Transport in Biological Systems
生物系统中工程调控的 RNA 定位和运输
  • 批准号:
    7981032
  • 财政年份:
    2010
  • 资助金额:
    $ 23.4万
  • 项目类别:
Investigating the Cytsolic Heme Pool in P. falciparum
研究恶性疟原虫胞质血红素池
  • 批准号:
    6915712
  • 财政年份:
    2004
  • 资助金额:
    $ 23.4万
  • 项目类别:
Investigating the Cytsolic Heme Pool in P. falciparum
研究恶性疟原虫胞质血红素池
  • 批准号:
    6738645
  • 财政年份:
    2004
  • 资助金额:
    $ 23.4万
  • 项目类别:
Investigating the Cytsolic Heme Pool in P. falciparum
研究恶性疟原虫胞质血红素池
  • 批准号:
    7061345
  • 财政年份:
    2004
  • 资助金额:
    $ 23.4万
  • 项目类别:
MINORITY PREDOCTORAL FELLOWSHIP PROGRAM--NIGMS
少数族裔博士前奖学金计划
  • 批准号:
    6388297
  • 财政年份:
    2001
  • 资助金额:
    $ 23.4万
  • 项目类别:
MINORITY PREDOCTORAL FELLOWSHIP PROGRAM--NIGMS
少数族裔博士前奖学金计划
  • 批准号:
    6181602
  • 财政年份:
    2000
  • 资助金额:
    $ 23.4万
  • 项目类别:
MINORITY PREDOCTORAL FELLOWSHIP PROGRAM--NIGMS
少数族裔博士前奖学金计划
  • 批准号:
    6155140
  • 财政年份:
    1999
  • 资助金额:
    $ 23.4万
  • 项目类别:
MINORITY PREDOCTORAL FELLOWSHIP PROGRAM--NIGMS
少数族裔博士前奖学金计划
  • 批准号:
    2796792
  • 财政年份:
    1998
  • 资助金额:
    $ 23.4万
  • 项目类别:

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开发疟原虫乙酰辅酶A合成酶抑制剂作为新型多级抗疟药
  • 批准号:
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受天然产物启发的具有根治潜力的新型抗疟药
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    10635649
  • 财政年份:
    2023
  • 资助金额:
    $ 23.4万
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具有耐药逆转功能的新型协同抗疟药
  • 批准号:
    10534667
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    2022
  • 资助金额:
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疟原虫蛋白激酶聚焦抗疟药的发现
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    10533634
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B-羟乙胺抗疟药的 DMPK 优化
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    2749037
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    2022
  • 资助金额:
    $ 23.4万
  • 项目类别:
    Studentship
Development of new lead antimalarials targeting parasite coenzyme A biosynthesis and utilisation.
开发针对寄生虫辅酶 A 生物合成和利用的新型先导抗疟药。
  • 批准号:
    468862
  • 财政年份:
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重新利用抗疟药治疗 NTM 感染
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    10368441
  • 财政年份:
    2022
  • 资助金额:
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