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Tackling Malaria Resistance with an Integrated Modeling/Experimental Approach

通过综合建模/实验方法应对疟疾耐药性

基本信息

批准号：
9111465
负责人：
Jennifer Lynn Guler
金额：
$ 23.2万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2016-08-15 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9111465
关键词：
Anabolism Antimalarials Appearance Artemisinins Atovaquone resistance Binding Biochemical Biochemical Pathway Biological Assay Bypass Cell physiology Cessation of life Clinical Computer Simulation Computing Methodologies Coupled Critical Pathways Data Dependency Development Dihydroorotate dehydrogenase Disease Drug Targeting Drug resistance Electron Transport Complex III Enzymes Experimental Designs Experimental Models Future Generations Genome Genomics Goals Human In Vitro Investigation Laboratories Lead Malaria Membrane Metabolic Metabolic Pathway Metabolism Methods Minor Mitochondria Modeling Mutate Mutation Organism Parasite resistance Parasites Pathway interactions Pharmaceutical Preparations Plasmodium falciparum Positioning Attribute Prevention Proteins Pyrimidine Reaction Recycling Refractory Resistance Resistance development Risk Stress System Systems Analysis Therapeutic Ubiquinone Work artemisinine atovaquone base biological adaptation to stress clinically relevant in vitro Assay in vitro testing inhibitor/antagonist metabolomics new therapeutic target novel pathogen prevent public health relevance reconstruction respiratory treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Malaria is responsible for almost a million deaths per year across the world. Plasmodium falciparum, the causative agent of the most deadly form of this disease, can readily develop resistance when treated with antimalarial drugs. Laboratory-reared resistant lines allow us to study how these parasites survive during drug challenge and help to inform more successful treatment strategies. Both clinical and laboratory investigations reveal that resistant parasites have specific changes in their genome that lead to excess amounts of the target protein (through genomic amplification) or the physical prevention of drug binding (through mutations). Because metabolism within an organism is highly interconnected with all cellular processes, pathways that interact with the mutated target must also make adjustments to support the parasite's continued ability to thrive. Some of these metabolic shifts may be minor and go unnoticed while others could confer unexpected benefits such as cross-resistance to additional drugs. This proposal describes a multifaceted approach to uncover and then impede these metabolic shifts that "enhance" parasite survival. Using an existing experimental system in which cross-resistance between two clinically-relevant antimalarials was observed, we will: 1) employ metabolomics data to construct a biologically accurate metabolic network reconstruction of the parasite before and after the generation of resistance in order identify metabolic dependencies of the resistant state and 2) computationally and empirically interrogate these critical pathways to determine if their abrogation can prevent P. falciparum resistance. Given that this work involves the disease-causing organism, which is refractory to experimental manipulation, computational models help to focus hypotheses and experimental design and mitigate risk. Additionally, since we are working with a validated experimental system and the approach takes advantage of expertise of the co-PIs involved in this proposal, we are well-positioned to rapidly build a pipeline of effective computational and experimental approaches. Once this is achieved, investigations can expand to uncover metabolic modulators of other clinically-relevant antimalarials. The ultimate goal will be to compile results from varios experimental systems and identify pathways that are required for parasite survival under stress. Targeting the general stress response would limit the development of resistance and have wide- reaching implications. A promising "resistance blocker" could be administered alongside relevant antimalarial drugs to prolong their effects and decrease worldwide malaria deaths.