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Dissecting the role of mitochondria division in cell cycle control of P. falciparum and drug resistance profiling of resistant strains

Grant number: 17/16307-9
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): March 01, 2018
Effective date (End): September 30, 2019
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Célia Regina da Silva Garcia
Grantee:Pedro Henrique Scarpelli Pereira
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated scholarship(s):18/06729-6 - Dissecting the molecular mechanism for activation of Plasmodium falciparum serpentine receptor 12 in mammalian systems, BE.EP.DD

Abstract

The initial hypothesis of the work reported in 2014-2016 is that melatonin, the host hormone that accelerates the maturation of P. falciparum during the intra-erythrocytic cycle, would have action on some mechanism of mitochondrial division. This hypothesis was formulated because cell division is accompanied by mitochondrial fission to form new cells. In this way, melatonin would accelerate both cell division and division of this organelle. Preliminary results indicated that second messengers such as melatonin and Ca2+ might indeed mediate mitochondrial division. This conclusion was established because messenger RNA expression data indicated that both melatonin and Ca2+ were able to alter the gene expression of the major effectors of the mitochondrial division genes, FIS1 (Mitochondrial Fission Protein) and the candidate DRP1 (Dynamin Related Protein), called DYN1 and/or DYN2. The same analyzes were carried out on the P. falciparum knockout line for protein kinase 7, which showed that this line does not present alterations in the expression of the same genes after the treatments with melatonin, in addition to not having an increase of the expression along the line erythrocytic cycle. This work allowed us to question the function of melatonin and the kinase 7 protein in the process of mitochondrial dynamics. Genome editing experiments proposed here will give enough data to establish a model that links mitochondrial fission and melatonin signaling. During the last semester, the candidate had the opportunity to do a research internship in Prof. David A. Fidock laboratory, in Columbia University Medical Center - New York, USA, with the aim of learning modern techniques of molecular biology and drug assays with P. falciparum. During this period, a collaborative project was developed to test the antibiotic azithromycin as an antimalarial in resistant strains isolated from Southeast Asia. Eight strains of different parasites were tested, two of them multiresistant to all currently used antimalarials. The IC 50 value for each lineage was calculated after incubation with azithromycin, artemisinin, chloroquine and piperaquine. The results reported here indicate that multidrug-resistant parasites against conventional antimalarials have an IC50 value higher than parasites resistant to only one or two conventional antimalarials. (AU)