Molecular pathways affected by drugs that disrupt Na+ and lipid homeostasis in malaria parasites
破坏疟原虫中钠和脂质稳态的药物影响的分子途径
基本信息
- 批准号:10659924
- 负责人:
- 金额:$ 71.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-05 至 2027-12-31
- 项目状态:未结题
- 来源:
- 关键词:ATP phosphohydrolaseActive Biological TransportAffectAntimalarialsBiochemicalBiologicalBiologyCarbonCell CycleCell membraneCellsChemicalsCholesterolCholesterol HomeostasisChromosome SegregationClinical TrialsCollectionComplexCytolysisCytoplasmDNA metabolismDevelopmentDrug TargetingDrug resistanceEnzymesEventExposure toFatty AcidsFundingGeneticGoalsHomeostasisHomoKnowledgeLipidsMalariaMembraneMetabolicMetabolismMolecularMorphologyParasitesPathway interactionsPatientsPediatric HospitalsPharmaceutical PreparationsPhasePhenotypePhiladelphiaPhysiologyPlasmodiumPlasmodium falciparumPlayProcessProtein DephosphorylationProtein phosphataseProteinsResearch PersonnelRoleSignal TransductionSodiumStructureUniversitiesWorkdrug discoveryfatty acid transportgenetic manipulationinhibitorinsightinterdisciplinary approachlipid transportnuclear divisionprematurepreventrecruitresponserhoptrysmoothened signaling pathway
项目摘要
Project Summary
In recent years, several chemically diverse compounds have been identified that target PfATP4, a P-type
ATPase involved in maintaining Na+ homeostasis in malaria parasites. Some of these compounds have
advanced to clinical trials. Thus, PfATP4-active compounds are among the most attractive new antimalarials
being developed to counter the continuing threat of drug resistance. Over the previous funding period, we have
discovered some dramatic alterations in parasite physiology that accompany a short 2 h exposure to PfATP4
inhibitors. These include: i) Rapid alterations in lipid homeostasis within the parasites with reversible
accumulation of cholesterol in the parasite plasma membrane (PPM); ii) Morphological changes resembling
premature schizogony; and iii) Massive dephosphorylation of parasite proteins that may underlie the metabolic
slowdown that follows PfATP4 inhibition. These observations reveal a collection of hitherto unknown interrelated
molecular pathways, disruptions of which result in parasite demise. We found that PfATP4 inhibition appears to
result in inhibition of PfNCR1, another druggable transporter, that is involved in maintaining lipid/cholesterol
homeostasis within the PPM. Reduction of cholesterol content of the RBC plasma membrane results in dramatic
expulsion of trophozoites from the host cell without the lysis of the RBC membrane. Remarkably, treatment with
either PfATP4 or PfNCR1 inhibitors prevents this expulsion. These studies suggest an active transport of
cholesterol between the RBC plasma membrane and the parasite. We found that trophozoite stage parasites
exposed to PfATP4 inhibitors for just 2 h undergo massive morphological changes that resemble premature
onset of schizogony events including the formation of inner membrane complexes, rhoptry-like structures and
karyokinesis. In addition, trophozoites undergo massive reduction of a large number of metabolites suggestive
of metabolic shutdown. We hypothesize that underlying all these events is a signaling cascade unleashed by
the influx of Na+ into parasite cytoplasm following PfATP4 inhibition. In support of this proposition, we found
dephosphorylation of a large number of proteins, prominent among which were molecules involved in DNA
metabolism, chromosome segregation and cell cycle processes. The complexity of events triggered by PfATP4
inhibition requires a multidisciplinary approach. For this purpose, we have recruited outstanding co-investigators
in consortium arrangements for the next funding period. Together, we propose to carry out the following specific
aims: i) Investigate the relationship between cholesterol dynamics and its role in fatty acid and lipid transport in
P. falciparum; ii) Explore the significance of dephosphorylation of proteins that follows PfATP4 inhibition; iii)
Examine the causes of metabolic slowdown following PfATP4 inhibition; iv) Derive structural information for
PfATP4 and PfNCR1 to understand molecular details about these validated antimalarial drug targets.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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AKHIL B VAIDYA其他文献
AKHIL B VAIDYA的其他文献
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{{ truncateString('AKHIL B VAIDYA', 18)}}的其他基金
Molecular Pathways Affected by Drugs that Disrupt Na+ Homeostasis in Malaria Parasites
破坏疟原虫 Na 稳态的药物影响的分子途径
- 批准号:
9364295 - 财政年份:2017
- 资助金额:
$ 71.2万 - 项目类别:
Molecular Pathways Affected by Drugs that Disrupt Na+ Homeostasis in Malaria Parasites
破坏疟原虫 Na 稳态的药物影响的分子途径
- 批准号:
9913475 - 财政年份:2017
- 资助金额:
$ 71.2万 - 项目类别:
Molecular Pathways Targeted by Potent Antimalarial Pyrazole Compounds
有效抗疟吡唑化合物靶向的分子途径
- 批准号:
8416318 - 财政年份:2012
- 资助金额:
$ 71.2万 - 项目类别:
Molecular Pathways Targeted by Potent Antimalarial Pyrazole Compounds
有效抗疟吡唑化合物靶向的分子途径
- 批准号:
8320487 - 财政年份:2012
- 资助金额:
$ 71.2万 - 项目类别:
Molecular Pathways Targeted by Potent Antimalarial Pyrazole Compounds
有效抗疟吡唑化合物靶向的分子途径
- 批准号:
8605504 - 财政年份:2012
- 资助金额:
$ 71.2万 - 项目类别:
Tools for Genomic Investigations of Plasmodium vivax
间日疟原虫基因组研究工具
- 批准号:
7145646 - 财政年份:2006
- 资助金额:
$ 71.2万 - 项目类别:
Tools for Genomic Investigations of Plasmodium vivax
间日疟原虫基因组研究工具
- 批准号:
7232437 - 财政年份:2006
- 资助金额:
$ 71.2万 - 项目类别:
BIOENERGETICS AND PROTON PUMPS IN MALARIA PARASITES
疟疾寄生虫中的生物能量学和质子泵
- 批准号:
7002735 - 财政年份:2003
- 资助金额:
$ 71.2万 - 项目类别:
BIOENERGETICS AND PROTON PUMPS IN MALARIA PARASITES
疟疾寄生虫中的生物能量学和质子泵
- 批准号:
6760043 - 财政年份:2003
- 资助金额:
$ 71.2万 - 项目类别:
BIOENERGETICS AND PROTON PUMPS IN MALARIA PARASITES
疟疾寄生虫中的生物能量学和质子泵
- 批准号:
6836481 - 财政年份:2003
- 资助金额:
$ 71.2万 - 项目类别: