Harnessing the Pathophysiology of Annexin A1 to Guide Translation and Therapeutic Application

• Grant number: 24/15297-3
• Support Opportunities: Research Projects - Thematic Grants
• Start date: July 01, 2025
• End date: June 30, 2030
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Sandra Helena Poliselli Farsky
• Grantee: Sandra Helena Poliselli Farsky
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Cristiane Damas Gil
• Associated researchers: Andrea Vieira ; Christiaan Reutelingsperger ; Fernando Gabriel Chirdo ; Lionel Fernel Gamarra Contreras ; Marcia Carvalho de Abreu Fantini ; Mauro Perretti ; Otávio Cabral Marques ; Pedro Leonidas Oseliero Filho ; Silvya Stuchi Maria-Engler

Abstract

Annexin A1 (AnxA1) is a Ca²¿-regulated phospholipid-binding protein secreted by epithelial, cancer, and immune cells to mediate survival, proliferation, apoptosis, differentiation, and migration. AnxA1 is found in the cytoplasm, mostly associated with vesicular structures, and is distributed throughout the cell and at the inner leaflet of the plasma membrane. It is translocated into the nucleus, although the precise mechanism of translocation and the functional relevance of nuclear AnxA1 are not fully understood. Secreted AnxA1 binds to G-protein-coupled seven-transmembrane domain receptors known as formyl peptide receptors. Strong evidence shows that secreted AnxA1 is a non-redundant mediator of the development and resolution of inflammation, thus regulating the host response to injury and pathogens. Conversely, the dampening or mitigation of the immune system can be detrimental in cancer, as intracellular and nuclear actions of AnxA1 on cancer cells favor disease progression. Therefore, while there is a rationale to apply AnxA1 or AnxA1-based approaches to protect and regulate tissue inflammation, this mediator needs to be blocked in settings of solid tumors and metastasis. As proof-of-concept for AnxA1's role in disease genesis and dual therapeutic exploitation (i.e., mimetics or blockers), we will test it in four different, yet overlapping, diseases: i) primary and metastatic melanoma; ii) inflammatory bowel disease; iii) chronic kidney disease; iv) Alzheimer's disease and neuroinflammation. These experimental settings have been selected based on our expertise and track record, as well as the need to better understand the etiopathogenesis and address the lack of effective therapies. An integrated approach will be used involving AnxA1 knockout cells and mice, antibodies, receptor antagonists, peptidomimetics, and nano-carriers to optimize delivery and efficacy of AnxA1 peptidomimetics. This project aims to deliver new discoveries and translational science that will pave the way for further development and therapeutic innovation in these exemplary diseases. Novel experimental protocols and scientific background will be required, as the proposal involves specialized expertise in the laboratory. Thus, the involvement of post-doctoral fellows and national and international collaborators will help overcome project challenges. The project is expected to educate undergraduate and graduate students, focusing on international collaborations for student exchange, and disseminate data in high-level journals and scientific meetings. (AU)