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.

Public Health Relevance

(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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI087874-03
Application #
8274768
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Mcgugan, Glen C
Project Start
2010-07-01
Project End
2013-09-30
Budget Start
2012-06-01
Budget End
2013-09-30
Support Year
3
Fiscal Year
2012
Total Cost
$132,300
Indirect Cost
$9,800
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Farrell, Andrew; Thirugnanam, Sivasakthivel; Lorestani, Alexander et al. (2012) A DOC2 protein identified by mutational profiling is essential for apicomplexan parasite exocytosis. Science 335:218-21