Investigation of the inflammasome formation in patients with sickle cell anemia

• Grant number: 16/08729-8
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): August 01, 2016
• Effective date (End): December 31, 2018
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Nicola Amanda Conran Zorzetto
• Grantee: Rafaela Mendonça Baggio
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 14/00984-3 - Red blood cell disorders: pathophysiology and new therapeutic approaches, AP.TEM
• Associated scholarship(s): 17/17878-0 - Activation of inflammatory caspases in sickle cell anemia: Role of leukocytes and the circulating milieu, BE.EP.DD

Abstract

Sickle Cell Anemia (SCA) has a complex pathophysiology that results in a chronic inflammatory state, which plays a fundamental role in the initiation and propagation of the vaso-occlusive processes that are associated with the disease, as well as many of its variable manifestations, such as acute chest syndrome, pulmonary hypertension, stroke and nephropathy. It is probable that the chronic inflammatory state in SCA occurs as the result of intravascular hemolysis and ischemia/reperfusion events. Consequently, the vaso-occlusive process is initiated by the adhesion of red blood cells and activated leukocytes to the activated endothelium of the microcirculation, forming a physical barrier to blood flow. Hydroxyurea (HU) is the only drug currently approved by the US Food and Drug Agency for use in adults with SCA; this drug modifies the disease process, improving hematological parameters in patients and reducing painful vaso-occlusive crisis frequency and time of hospitalization. We believe that the formation of the inflammasome complex in the leukocytes of patients with SCA may potentially contribute significantly to the inflammatory state in this disease. The inflammasome is a multiprotein complex formed in inflammatory cells, consisting of a sensor molecule, NLRP3, a caspase-1 adapter protein named ASC (Apoptosis associated speck like protein containing a CARD) and caspase-1. The formation of the inflammasome may be stimulated by a series of molecules that are released during infections or tissue damage. These molecules are known as Pathogen Associated Molecular Patterns (PAMPs) and danger associated molecular patterns (DAMPs), respectively. This project aims to confirm the existence of inflammasome formation in the neutrophils and monocytes of patients with SCA (in patients taking and not taking HU therapy) and to identify the components of this complex, as well as the potential DAMPs involved in their formation in this disease. We intend to use techniques such as ELISA, Western blotting, flow cytometry, confocal microscopy and imaging cytometry (Amnis® Milipore) for this investigation, with the aim of identifying therapeutic targets and approaches for limiting the inflammatory state in SCA. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

BAGGIO, Rafaela Mendonça. Investigation of inflammasome formation in sickle cell anemia patients. 2019. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas Campinas, SP.