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Molecular analysis of a kinase essential for replication of Plasmodium falciparum

恶性疟原虫复制所必需的激酶的分子分析

基本信息

批准号：
7868632
负责人：
JEFFREY D DVORIN
金额：
$ 13.23万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7868632
关键词：
Advisory Committees Affinity Age-Years Antimalarials Biochemical Biological Biological Process Biology Blood Boston Calcium Candidate Disease Gene Cells Cessation of life Child Mortality Clinical Commit Data Development Plans Drug Delivery Systems Drug resistance Environment Enzymes Epitopes Erythrocytes Evaluation Faculty Family Future Genes Genetic Goals HIV Human Human Genome Immunoelectron Microscopy Immunofluorescence Immunologic In Vitro Incubated Infection Knock-out Life Cycle Stages Malaria Mass Spectrum Analysis Mediating Mentorship Molecular Molecular Analysis Molecular Biology Palmitic Acylation Site Parasites Parasitology Pathogenesis Pathway interactions Pattern Pediatric Hospitals Peptide Hydrolases Pharmaceutical Preparations Phosphorylation Phosphotransferases Plants Plasmodium falciparum Positioning Attribute Process Proteins Proteomics Public Health Schools Recombinants Regulation Reporting Research Resistance Resistance development Role Scanning Signal Transduction Staging System Techniques Testing Text Therapeutic Time Training Transgenic Organisms Tropical Medicine Vaccines Work abstracting asexual base calcium-dependent protein kinase career career development design enzyme activity experience genetic manipulation in vivo novel pathogen preference prevent programs protein transport research study trafficking

项目摘要

DESCRIPTION (provided by applicant): NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== Malaria is the fourth leading cause of mortality for children under five years of age globally, with most of these deaths resulting from Plasmodium falciparum. A molecular understanding of the life cycle of P. falciparum will facilitate the rational design of new therapies. P. falciparum requires efficient invasion into and egress out of human erythrocytes during the asexual replication stage of the parasite life cycle. Our preliminary data have identified a plant-like calcium-dependent protein kinase PfCDPK5 that is crucial for P. falciparum egress. These experiments have generated the first functional knockout of an essential blood-stage gene in P. falciparum. PfCDPK5-deficient parasites arrest at a very late-stage of the intra-erythrocytic life cycle. We hypothesize that PfCDPK5 mediates a critical calcium-dependent signal required for P. falciparum egress. The goals of this proposal are to gain a better understanding of PfCDPK5 function and elucidate its role in parasite egress from infected erythrocytes. In the first aim, the candidate will determine the localization, trafficking, and regulation of this essential kinase. Using two mass spectrometry based techniques and a third candidate gene approach, the experiments of the second aim will identify the in vivo substrate(s) of PfCDPK5. These studies will be conducted under the mentorship of Dr. Dyann Wirth, a pioneer in P. falciparum genetics and mechanisms of drug resistance, and the co-mentorship of Dr. Manoj Duraisingh, an expert in P. falciparum genetic manipulation and molecular biology. In addition to the proposed experiments, the candidate's career development goals are to gain expertise in parasitology, P. falciparum molecular biology, and tropical medicine. These immediate goals will be achieved by attending formal courses in proteomics, parasite biology, and tropical medicine and by receiving mentorship and guidance from his scientific advisory committee. The candidate's long-term career goals are to attain a tenure-track faculty position and to continue his research on the molecular pathogenesis of malaria. The training opportunities at the Harvard School of Public Health together with the mentorship of Drs. Wirth and Duraisingh are an ideal environment for this career development program. Children's Hospital Boston is committed to this career development plan and has assured that the candidate will be able to devote at least 75% full-time effort to the activities described in this proposal. (Relevance): Malaria is the fourth leading cause of mortality for children under five years of age globally, with most of these deaths resulting from Plasmodium falciparum infection. The goal of this application is gain a better understanding of the molecular mechanisms of P. falciparum replication in human red blood cells. Using genetic and biochemical techniques, this project will characterize the key biological process of parasite egress from red blood cells and ultimately identify new targets for future anti- malarial medications.

描述（由申请人提供）：