Ricerca Progetti nazionali, regionali, internazionaliNAZIONALIPRIN 2022Insight into the molecular mechanisms

Insight into the molecular mechanisms of pulmonary fibrosis: new targets to control the switch from fibrotic to regenerative fibroblast phenotype - SMILE

Progressive pulmonary fibrosis is the hallmark of Idiopathic pulmonary fibrosis (IPF) and other Interstitial lung diseases (ILDs). IPF is a non-neoplastic pulmonary rare disease characterised by the lung epithelial transformation, accumulation of myofibroblasts and deposition of extracellular matrix boosted by immune system activation, which progressively leads to respiratory failure. So far, only two anti-fibrotic drugs have been approved to reduce IPF progression with a limited survival advantage. Despite several decades of research, the mechanisms orchestrating the induction and maintenance of fibrosis in the lung are still unclear. Recently, besides the central role played by fibroblasts, other mechanisms have emerged such as the activation of neutrophils and the formation of neutrophil extracellular traps (NETs). In this complex scenario, the project aims to identify new biochemical and molecular features able to tune the main processes involved in disease progression, opening the way to the development of novel therapeutic strategies. Many soluble cues in the extracellular microenvironment affect cell responses. Among these, extracellular adenosine (ADO) and sphingosine 1-phosphate (S1P) can have positive or detrimental effects based on concentrations and target cells, making their involvement in fibrosis puzzling. In human fibrotic lung diseases, dynamic changes in myo-, and lipo- fibroblasts suggest differential requirements for injury pathogenesis and repair. The first aim of the project will be to investigate the role of ADO and S1P in tuning

the phenotype of fibroblasts directing the fibrotic process. Although the investigation of molecular mechanisms in a single cell type is fundamental, there is an increasing need for advanced models. Herein, co-culture cellular models will be used to dissect the role of ADO/S1P in the cross-talk between the immune cells, specifically activated neutrophils, and fibroblasts to orchestrate the progression of the fibrotic process.

The active collaboration between basic researchers and clinicians will allow translating the research from the bench to the bedside. The correlation between the alteration of ADO/S1P signalling in the immune response and the clinical stage of IPF patients will be the second aim of the project. This will hopefully allow identifying early biomarkers of pathology and planning the initial stage of therapeutic interventions that may improve patient lifestyle and disease outcome. Ultimately, the project findings will likely pave the way for the identification of unrecognized therapeutic targets able to block or slow the progression of this rare, progressive, and fatal disease with a relevant social impact. In this respect, our proposal is totally aligned with the priorities of the Research and Innovation actions funded by the EU, which aim to improve the lives of patients with rare diseases through supporting basic research as a pivotal ground for translational research.

 

Data di avvio 5 Ottobre 2023

Data di completamento 5 Ottobre 2025

Total cost  € 109060,00

 

Progetto 2022NAFK8C finanziato all’interno del Bando PRIN 2022 di cui al Decreto Direttoriale n. 104 del 02/02/2022 nell’ambito del Piano Nazionale di Ripresa e Resilienza, Missione 4 – Componente 2. Dalla Ricerca all’Impresa - Investimento 1.1 Fondo per il Programma Nazionale della Ricerca (PNR) e Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN), finanziato dall’Unione europea – NextGenerationEU – CUP B53D23016410006