Evaluation of Inflammasome Activation in Cells of Patients with Autoinflammatory Disease and Its Correlation with Individual Genetics

• Grant number: 23/17878-0
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2024
• End date: July 31, 2026
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Alessandra Pontillo
• Grantee: Alessandra Pontillo
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Bruna Cunha Gondim de Alencar ; Leonardo Oliveira Mendonça ; MARIELA ESTEFANY GISLENE VERA ROA ; Vinícius Nunes Cordeiro Leal
• Associated scholarship(s): 24/23297-3 - Selection of Rapid Protocols for Diagnostic Confirmation of Patients with Autoinflammatory Syndromes CAPS, BP.IC; 24/20620-8 - Evaluation of Inflammasome Activation in Cells of Patients with Autoinflammatory Disease and Its Correlation with Individual Genetics, BP.TT

Abstract

Monogenic inflammasomopathies constitute a group of rheumatological disorders stemming from dysregulation of the inflammasome complex caused by gain-of-function mutations in inflammasome genes or molecules that indirectly affect its activation. The prototypes of this group of diseases are the Cryopyrin-Associated Periodic Syndrome (CAPS) and Familial Mediterranean Fever (FMF), associated with NLRP3 and pyrin receptors, respectively. Pathogenic variants in a gene can present with variable expressivity and incomplete penetrance or be inherited in a recessive or dominant manner, resulting in distinct phenotypes. The disease presentation is also defined by the specific effect of the mutant protein on a particular cell type, potentially making the resulting phenotype more harmful in one tissue than in another. While genetic testing is crucial for confirming the diagnosis, it is not always conclusive and informative regarding phenotypic variability, prognosis, and treatment response. In middle- and low-income countries like Brazil, widespread access to genetic testing is still limited.In this project, we propose a mixed approach of transcriptomics and functional proteomics to investigate leukocytes and specific mutations identified in Brazilian patients. Thus, we aim to characterize genotype-phenotype correlations in typical and atypical cases, intending to develop tools that enhance the diagnosis and treatment of these diseases while simultaneously deepening our understanding of inflammasome regulation. (AU)