Characterization of CRK1 kinase in the control of cell proliferation and metacyclogenesis of Trypanosoma cruzi

• Grant number: 22/08866-6
• Support Opportunities: Scholarships in Brazil - Master
• Start date: May 01, 2023
• End date: July 31, 2024
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Simone Guedes Calderano
• Grantee: Artur da Paixão Corrêa
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 20/00694-6 - How DNA replication contributes for the success of infection caused by Trypanosoma cruzi, AP.TEM

Abstract

CDKs (cyclin dependent kinases) are kinases that work together with cyclins to regulate the cell cycle in model eukaryotes. Through the action of these kinases, cells can progress through the cell cycle or enter quiescence, depending on the nutritional conditions of the environment and the presence of mitogenic stimuli. The entry into quiescence is important for cell survival under unfavorable conditions and plays an important role in cellular resistance to chemotherapy treatments (in cancer cells, yeast and pathogenic organisms). Throughout the life cycle of Trypanosoma cruzi, which causes Chagas Disease, different forms of life are found in the invertebrate vector and in the mammalian host. These forms meet different environmental conditions to which they are adapted and thus differ from each other in terms of morphology, metabolic profile and replicative capacity. Replicative forms differentiate into infective forms that are unable to replicate, and in this transition, nutritional stress is an important factor that triggers entry into quiescence and subsequent differentiation. Another aspect of proliferative control in T. cruzi is the role of the replicative rate in drug resistance, where parasites resistant and persistent to benznidazole treatment (in vitro and in vivo) have lower replicative rates. Knowing the importance of proliferative control for the life cycle of T. cruzi and drug resistance, this project proposes to investigate CRK1 (cdc2 related kinase), a homolog of CDK1, which is involved in cell cycle control. The objective will be to understand the mechanism of action of CRK1 in the control of cell proliferation and in the transition to quiescent infective forms during metacyclogenesis. Using cutting-edge methodologies such as CRISPR/Cas9 and TurboID, the repertoire of CRKs interactors in proliferating cells and at entry into quiescence during metacyclogenesis will be identified. The results obtained will represent a substantial advance in the knowledge about the functions of CRKs, not only as regulators of cell proliferation, but also in other functions throughout the life cycle of T. cruzi.