Mecanismos de Regulação da Biogénese do Granuloma na Sarcoidose

Our project aims to uncover the molecular and cellular mechanisms that underlie the intricate pathogenesis of sarcoidosis and identify new targets for diagnostic, prognostic, and therapeutic intervention. Our preliminary findings support a novel pathogenetic model for sarcoidosis, wherein a dysfunctional phagosome maturation impairs microbial killing and, in turn, licenses the activation of detrimental molecular and metabolic signatures that promote granuloma formation. Therefore, our primary goal is to identify and delineate the molecular and cellular sequences of events that link the defective phagosomal dynamics in sarcoidosis with functional features of macrophages, and how this drives granuloma formation and influences the clinical course of sarcoidosis. To achieve this, we assembled a multidisciplinary team of internationally recognized experts on molecular and cellular biology, immunology, microbiology, metabolism, and clinical specialists in interstitial lung disease that will employ a translational approach combining state-of-the-art research tools in advanced preclinical cellular models and human patients within the FIBRALUNG cohort. Our specific objectives are to: [1] Define the molecular regulation of phagosomal dynamics in sarcoidosis. We will investigate the molecular mechanisms involved in the regulation of phagosome biogenesis and maturation in macrophages at the single-cell level and with spatiotemporal resolution. [2] Evaluate the functional crosstalk of humoral innate immunity and phagosomal dynamics. We will analyze the molecular interactions among specific components of humoral innate immunity in phagosomal dynamics and their contribution to the functional and metabolic activity of macrophages. [3] Validate the role of phagosomal dynamics in granuloma formation. We will employ a strategy based on the generation of primary models for giant cell differentiation and cellular aggregation, along with systematic functional analyses to explore how phagosomal activity regulates granuloma formation. [4] Describe the role of phagosomal dynamics in the clinical phenotype of sarcoidosis. We will integrate molecular markers of defective phagosomal dynamics in sarcoidosis with clinical and immunological data using computational approaches to define individual disease trajectories and contribute to personalized therapeutic decisions. The ambitious and innovative approach within our project has a strong translational emphasis, advancing from a molecular perspective on phagosomal dynamics in diseased cells to the comprehensive phenotyping of disease-relevant models and the clinical evaluation of its contribution to disease progression and the response to therapy. Our project is therefore poised to significantly advance the state-of-the-art and provide new insights into our understanding of granulomatous inflammation, with profound implications for the clinical management of sarcoidosis. Our long-term goal of improving clinical outcomes will be achieved by harnessing the acquired knowledge to propel research beyond the duration of the project. We specifically plan to accomplish this by designing and conducting prospective clinical trials to evaluate the prognostic performance of a multivariate risk model for estimating disease trajectory and predicting treatment responses in sarcoidosis. In conclusion, this project represents a critical step towards personalized care in sarcoidosis and granulomatous diseases in general.