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Studying telomere homeostasis in Leishmania spp. by using Hsp90 and telomerase inhibitors

Grant number: 12/25475-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2013
Effective date (End): September 30, 2016
Field of knowledge:Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
Principal researcher:Maria Isabel Nogueira Cano
Grantee:Marcela Segatto Do Carmo
Home Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
Associated research grant:12/50161-8 - Study of the structure and function of the Hsp90 chaperone with emphasis on its role in cellular homeostasis, AP.TEM

Abstract

Leishmaniasis are chronic diseases caused by flagellated protozoa of the Leishmania genus. Disease's treatment consists in the administration of pentavalent antimonials, which besides the high toxicity to the patients also records considerable failure. Therefore, the success of leishmaniasis treatment requires new therapeutic strategies and recently, telomeres have been considered a potential target for drug development. Telomeres are DNA:protein complexes responsible for protecting the ends of eukaryotic chromosomes. Chaperones have been related to the stability of some telomeric components, since in yeast and human it directly interacts with telomerase, increasing enzyme stability and improving telomerase activity. One of the most abundant and essential chaperones, Hsp90, participates of the assembly and maturation pathways of several cellular complexes, such as telomerase. Telomerase is a ribonucleoprotein complex directly involved in the telomere replication and maintenance. Among trypanosomatids, the L. amazonensis telomeric complex is the better characterized and telomerase activity has been already demonstrated as well as the presence of a very active Hsp83 (the parasite Hsp90 ortholog). The hypothesis to be tested in the present proposal is based on the fact that Hsp90 in synergy with telomerase form a complex involved in Leishmania spp. telomere homeostasis. We aim to evaluate the possible interactions between the Hsp83 and its co-chaperone p23 with the parasite telomeric chromatin, and more directly with the telomerase component of L. amazonensis (LaTERT). In addition, using the efficient method of quantitative PCR (qPCR), we are going to estimate alterations in telomere size in both promastigotes and amastigotes forms, exposed to the Hsp90 inhibitor - 17-AAG. The same analysis will be conducted using the telomerase inhibitor - BIBR1532. We believe that these approaches will be precious tools to the comprehension of telomeres biology and homeostasis in trypanosomatids.