Dissecting signaling pathways in the Plasmodium-host relationship for the search of new drugs

• Grant number: 23/07656-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: September 01, 2025
• End date: August 31, 2030
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: Célia Regina da Silva Garcia
• Grantee: Célia Regina da Silva Garcia
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Ronaldo Fumio Hashimoto
• Associated researchers: Carlos Alberto Montanari ; Márcio Weber Paixão

Abstract

Using genetic tools, we have identified the role of the kinases PfeIK1, PfPK7, and the nuclear protein PfMORC in coordinating the development of the Plasmodium falciparum etiologic agent of malaria. Our research aims to elucidate the molecular machinery involved in the signaling pathways that act in the intraerythrocytic development of the parasite. In addition, we have constructed one of the first transgenic parasites to measure intracellular calcium concentration in real-time in P. falciparum (PfGCaMP3). Using machine learning and biochemical tools, we proposed that the MDR1(multi-drug resistance) protein acts as a receptor for IP3 in the parasite's digestive vacuole (DV). Regarding the upstream signaling pathway in P. falciparum, we identified four serpentine receptors (PfSR1, PfSR10, PfSR12, PfSR25) candidates for GPCR by bioinformatics. From the knockout of PfSR25, we report that this receptor is involved in the parasite's susceptibility to antimalarials. Thus, in this thematic project proposal and with the advances obtained in the current thematic project, we propose to study the signaling pathways of P. falciparum involved in the relationship between host and parasite to identify potential targets for drug development. Among the questions we seek to answer are: how do parasites detect environmental signals to trigger the process of differentiation, invasion, and egress from the host cell? Which cellular and molecular events modulate the Plasmodium cell cycle and control its synchronization and proliferation?The relevance of this proposal is based on the expertise of Prof. Celia R. S. Garcia, who has coordinated 6 FAPESP thematic projects and has a network of international and national collaborators to develop the project.The proposal is disruptive and interdisciplinary and includes the following principal investigators: mathematician Prof. Ronaldo Hashimoto, IME-USP, and synthetic chemist Prof. Márcio Weber from UFSCAR, and includes the use of several state-of-the-art methodologies that are widely used in laboratories in the USA, France, and Canada. (AU)