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PIEZO1 in sickle cell disease: Role in erythrocyte and inflammatory cell function

Grant number: 20/06133-6
Support type:Regular Research Grants
Duration: December 01, 2020 - November 30, 2022
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Cooperation agreement: Université de Lyon (UDL)
Principal researcher:Nicola Amanda Conran Zorzetto
Grantee:Nicola Amanda Conran Zorzetto
Principal researcher abroad: Philippe Connes
Institution abroad: Université Claude Bernard Lyon 1, France
Home Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Assoc. researchers: Céline RENOUX ; Elie Nader ; Fernando Ferreira Costa ; Flávia Costa Leonardo ; Nicolas Guillot ; Philippe JOLY
Associated scholarship(s):21/03686-7 - PIEZO1 in sickle cell disease: role in erythrocyte and inflammatory cell function, BP.TT

Abstract

Abstract: Sickle cell disease (SCD) is a group of inherited disorders, caused by mutations in the gene encoding ²-globin. The disease causes alterations in the hemoglobin molecule, resulting in altered red blood cell (RBC) properties and shape, and the destruction of these cells in the circulation, leading to anemia and other complications. The pathophysiological changes incurred from this alteration result in the several acute and chronic complications associated with the disease, including frequent painful vaso-occlusive episodes, auto-splenectomy, acute chest syndrome, priapism, pulmonary hypertension, leg ulcers, nephropathy, retinopathy, hepatopathy, osteonecrosis and cerebral stroke. Piezo1 is a protein with mechanosensitive properties that is involved in the cellular influx of calcium (Ca2+). Genetic mutations that increase sensitivity to Piezo1 have been shown to be responsible for hereditary xerocytosis, a disorder in which RBCs are severely dehydrated. In addition, Piezo1 plays an important role in cellular homeostasis in endothelial cells and platelets. Platelets and leukocytes are highly activated in SCD, promoting chronic and systemic oxidative and inflammatory stress in this disease, two factors involved in the development of acute complications and chronic organ damage. The aim of this project is to characterize the role of Piezo1 in 1) the dehydration of RBCs, sickling, eryptosis and adhesion; and in 2) the activation and adhesion of leukocytes and platelets in SCD. Molecules to modulate Piezo1 activity and high-tech methodologies (Imaging and classic flow Cytometry, microfluidic approaches, oxygen gradient ektacytometry, electrophysiology) available in the two partners' locations will be used to determine and describe the role that Piezo1 could play in RBC alterations and inflammation in SCD, and more generally in the pathophysiology of this disease. We anticipate that the results generated by this project could help in identifying a new molecular candidate for therapeutic approaches, in order to improve the health status of the patients. (AU)