Idiopathic Pulmonary Fibrosis and Megakaryocyte Alterations (PUMA)

Project objectives

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease that leads to fatal lung failure within 2 to 4 years. Despite the consensus that IPF is driven by genetic lesions, its etiology is far from established and there is currently no cure. Progress in the field is challenged by the limited availability of lung biopsies for studies (lung biopsy is associated with adverse outcomes) and its animal models are induced by environmental insults that are not the cause of disease in humans.
We found that the lungs of IPF patients contain abnormal megakaryocytes with low levels of the GATA1 transcription factor required for their maturation, and their blood contains high levels of megakaryocytes (20% vs <5% in normal individuals). Furthermore, mice carrying a mutation that reduces GATA1 expression in megakaryocytes (Gata1low) develop an IPF phenotype with age. Using these findings as a foundation, we propose to test the general hypothesis that IPF is driven by unknown “genetic” alterations in hematopoietic stem cells that reduce GATA1 expression in megakaryocytes generated from these lung-resident cells. These altered megakaryocytes secrete signaling factors (soluble or cell surface), yet to be identified, that activate TGF-β/CXCL1 production in the lung microenvironment, inducing fibrosis. This hypothesis will be tested by genetic and functional studies of megakaryocytes from the lungs of Gata1low mice and in surrogate human in vitro models using cells obtained from the blood of IPF patients. The blood cells will be collected under the umbrella of NOMAD, an observational study directed by our collaborator Prof. Richeldi, Fondazione Policlinico Gemelli, Rome, Italy, to define new biomarkers for disease prognosis/progression and targets for therapy in IPF.
The project is multidisciplinary and innovative, risky but with great potential to address currently unmet clinical needs. It also has potentially relevant implications for the pathobiology of a variety of pulmonary infectious diseases, including SARS-COV-

Start and end date

Project Manager

Coordinating institution of the project

Other institutions involved in the project

• Anna Rita Franco Migliaccio, Lecce, Italy
• Istituto Superiore di Sanità (ISS), Rome, Italy
• Luca Richeldi, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Catholic University of the Sacred Heart, Rome
• Alberto Rainer, Campus Bio-Medico University
• John Stam, Altius

Project funding source