Novel antimalarial strategies using metabolomic network discovery

利用代谢组学网络发现的新型抗疟策略

基本信息

批准号：
7426966
负责人：
Manuel Llinas
金额：
$ 237万
依托单位：
PRINCETON UNIVERSITY
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：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7426966
关键词：
Address Affect Affinity Agriculture Amino Acids Anemia Animal Model Antimalarials Anus Apicomplexa Architecture Area Arginine Arts Assimilations Attention Biochemical Biochemical Pathway Biochemical Reaction Biochemistry Bioinformatics Biological Biological Assay Biological Factors Biological Models Biology Bioreactors Blood Blood Cells Blood capillaries Brain CH3OCF2CH(CF3)OCH2F Carbon Cell Cycle Cell surface Cells Cerebral Malaria Cessation of life Charge Chemicals Chemistry Chromatography Chronic Class Clinical Code Collaborations Communities Complex Condition Coupled Couples Crude Extracts Culicidae Cytoplasm DNA Microarray Chip DNA Microarray format DNA Repair Data Data Analyses Data Set Databases Daughter Dependency Detection Development Developmental Process Diagnostic Discipline Disease Drug Delivery Systems Drug Design Drug resistance Economics Employee Strikes Ensure Environment Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Erythrocytes Escherichia coli Eukaryota Eukaryotic Cell Event Evolution Fatty Acids Fees Fever Figs - dietary Fluorescence-Activated Cell Sorting Foundations Fourier Transform Functional RNA Funding Future Gases Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genome Genomics Glucose Goals Green Fluorescent Proteins Growth Health Heat-Shock Response Heme Hemoglobin Hepatocyte High Pressure Liquid Chromatography Hour Housing Human Hybrids Hydrolase Gene Hypoglycemia Immobilized Cells Immune Immune system In Vitro Individual Infection Ingestion Institutes Intervention Invaded Investigation Ions Isotope Labeling Isotopes Kinetics Knock-out Knowledge Label Laboratories Lactic Acidosis Length Libraries Life Life Cycle Stages Link Liquid Chromatography Liquid substance Malaria Maps Mass Spectrum Analysis Measurement Measures Mediating Medical Metabolic Metabolic Pathway Metabolism Methanol Methodology Methods Microarray Analysis Microbe Modeling Molecular Molecular Biology Molecular Biology Techniques Molecular Profiling Molecular Structure Molecular Weight Monitor Mosquito Control Moths Mus Mutagenesis Mutation Nature Network-based Nitrogen Noble Gases Noise Nuclear Magnetic Resonance Nucleic Acids Numbers Nutrient Oligonucleotides Ontology Open Reading Frames Organic solvent product Organism Ornithine Decarboxylase Output Ozone Pain Parasite resistance Parasitemia Parasites Parasitology Parents Pathogenesis Pathway Analysis Pathway interactions Patients Pattern Personal Satisfaction Pharmaceutical Preparations Phenotype Plasmodium Plasmodium falciparum Plasmodium malariae Population Postdoctoral Fellow Printing Probability Procedures Process Production Property Protein Export Pathway Proteins Proteome Proteomics Purines Quantitative Trait Loci RNA Range Rate Reaction Recording of previous events Recycling Relative (related person)Reliance Reporting Reproducibility Research Research Personnel Resolution Resources Respiratory distress Retrieval Robotics Saccharomyces cerevisiae Sampling Scanning Science Series Signaling Molecule Software Tools Solvents Sorbitol Source Spectrometry Speed Staging Standards of Weights and Measures Statistical Models Stress Structure Students Study models System Systems Integration Techniques Technology Temperature Therapeutic Time Today Training Transcript Transfection Transgenic Organisms Universities Urination Variant Water Work Yeasts adenosine deaminase base capillary cell type chemical property cofactor comparative computer based statistical methods computer science cost data integration design drug development enzyme pathway experience extracellular fatty acid amide hydrolase flasks functional genomics gene function genome sequencing high throughput analysis improved innovation insight instrument interest ionization knowledge base mRNA Differential Displays mass spectrometer mecarzole medical specialties member metabolomics mutant novel novel therapeutics parasite genome pathogen post-doctoral training prevent programs promoter purine quantum reconstitution research study scaffold scale up small molecule social solvent extraction success sugar tandem mass spectrometry theories therapeutic target tissue culture tool trafficking transcriptomics trend uptake user-friendly

项目摘要

Malaria is a major global health issue affecting over half a billion people and resulting in 3-5 million deaths annually. This disease is caused by parasites of the genus Plasmodium with P. falciparum being the most lethal species. The host-pathogen relationship between Plasmodium and the host red blood cell is responsible for all clinical manifestations of the malaria disease and is a continuous 48-hour cycle that can be faithfully reproduced in the laboratory. Despite over a century of research on malaria, it continues to be a major health problem largely because drug-resistant parasites are on the rise, circumventing long-efficacious drug treatments. Thus, there is a renewed urgency to identify novel chemotherapeutics to treat this disease. This proposal aims to provide the first global analysis of the metabolic host-pathogen interactions for Plasmodium falciparum as a means to identify novel drug targets. The metabolic pathways encoded in any pathogen genome define the repertoire of chemical processes that it can autonomously regulate. All other metabolites must be taken up from the host cell or metabolized from precursors available through the host. Therefore, the host cell and pathogen are intimately linked through the reliance of the pathogen on the host for nutrients. The genome of P. falciparum suggests that this organism is biochemically unique: 60% of its genome encodes proteins never seen before in biology, and the remaining 40% contains very few of the fundamental metabolic genes found in almost all other eukaryotes. This indicates that the mechanism of interaction between Plasmodium and the host red blood cell may reveal novel metabolic enzymes that can provide new targets for pharmacological intervention. Using recently developed mass spectrometry techniques, we will quantitate metabolites in Plasmodium-infected cells and integrate these and other data to generate network interaction models revealing new biological insights into this deadly pathogen.

疟疾是全球主要的健康问题，影响了超过十亿人口，每年导致3-5万人死亡。该疾病是由该属的寄生虫引起的疟原虫和恶性疟原虫是最致命的物种。宿主病原体疟原虫与宿主红细胞之间的关系是所有的原因疟疾疾病的临床表现，是一个连续的48小时周期，可以忠实地在实验室中复制。尽管有一个多世纪的疟疾研究，但它仍然是一个主要的健康问题，主要是因为耐药的寄生虫正在持续上升，规避长期有效的药物治疗。因此，有一个更新识别新型化学治疗剂以治疗这种疾病的紧迫性。该建议旨在提供对代谢的首次全球分析恶性疟原虫的宿主 - 病原体相互作用作为一种手段识别新型药物靶标。在任何病原体中编码的代谢途径基因组定义了可以自主调节的化学过程的曲目。所有其他代谢物必须从宿主细胞中取走或从前体代谢可通过主机获得。因此，宿主细胞和病原体密切相关通过病原体在宿主上的依赖养分。 P.的基因组恶性法表明这种生物在生化上是独一无二的：其基因组的60％编码在生物学中从未见过的蛋白质，其余40％的蛋白质很少在几乎所有其他真核生物中发现的基本代谢基因。这表明疟原虫与宿主红细胞之间相互作用的机制可能揭示新的代谢酶，可以为药理学提供新的靶标干涉。使用最近开发的质谱技术，我们将定量疟原虫感染细胞中的代谢产物，并整合这些和其他数据为了生成网络交互模型，揭示了对这一致命的新生物学见解病原。

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）

Nutrient sensing modulates malaria parasite virulence.

DOI：
10.1038/nature23009
发表时间：
2017-07-13
期刊：
Nature
影响因子：
64.8
作者：
Mancio-Silva L;Slavic K;Grilo Ruivo MT;Grosso AR;Modrzynska KK;Vera IM;Sales-Dias J;Gomes AR;MacPherson CR;Crozet P;Adamo M;Baena-Gonzalez E;Tewari R;Llinás M;Billker O;Mota MM
通讯作者：
Mota MM

Central carbon metabolism of Plasmodium parasites.