The Trypanosoma cruzi is a flagellate protozoon that cause of Chagas disease in man. In its life cycle, T. cruzi presents a high capacity of environmental adaptation. However, the mechanisms that signal this adaptation are not yet well known. It possibly depends on the availability of nutrients. One of the main mechanisms involved in the control of the energy state of eukaryotes cells occurs by means of the protein kinase activated by the AMP increase (AMPK). This protein kinases phosphorylates different substrates, increasing energy production and the level of substrates by inducing autophagy. It has already been shown that the activation of AMPK Trypanosoma brucei promotes the differentiation of the replicative form into a quiescent form by inhibition of the kinase protein called "Target of Rapamycin 4" (TOR4). However, it has been shown that autophagy does not depend on the AMPK in T. brucei. Genes that encode homologous proteins to AMPK are also present in T. cruzi. Two catalytic subunits are found, but the role of each of them is still unknown in this parasite. In results obtained in our laboratory, we found activation of the subunit a1 AMPK during the induction of the differentiation of the parasite by nutrient starvation occurs. We also noticed that when the AMPK is inhibited in starving conditions, the parasite's cellular death occurs. Therefore, this project aims to examine the state of activation of AMPK in T. cruzi and whether it is necessary for differentiation and if this activation is related to the induction of autophagy in the parasite, already recognized as a relevant factor in differentiation.Therefore, we propose in this proposal:1.Confirm that the nutritional stress causes the activation of the AMPK and examine the activation state of the AMPK during the life cycle of the T. cruzi. 2.To verify the effects of the pharmacological inhibition of AMPK in the proliferation and differentiation of the parasite. 3.Generate parasites with stop mutations in the genes coding for the two catalytic subunits and verify the phenotypes of growth, differentiation and autophagy.This study will allow us to better understand how the T. cruzi responds to nutritional stress situations to adapt to different hosts.
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