Anti-fibrotic effects of the Mirlet7/NuRD ribonucleoprotein complex in idiopathic pulmonary fibrosis

• Applicant: Professor Guillermo Barreto, Ph.D.
• Subject Area: Pneumology, Thoracic Surgery ; Biochemistry
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 408916879

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and highly lethal interstitial lung disease with unknown etiology and with poor prognosis. IPF patients die within 2 to 5 years after diagnosis mostly due to respiratory failure. Lung tissues from IPF patients show fibroblastic foci that consist of expanded myofibroblast population and excessive extracellular matrix (ECM) protein deposition. Myofibroblasts are contractile activated fibroblasts that express α-smooth muscle actin (ACTA2) to facilitate wound closure after injury. However, persistent activation of these cells causes excessive deposition of ECM in the interstitial space that leads to fibrosis. The precise control of gene expression is essential for both expansions of activated fibroblasts after injury and dedifferentiation into resting fibroblasts after wound healing. During dedifferentiation of activated fibroblast into resting fibroblast, the balance between transcription of lineage specific genes and repression of pro-fibrotic genes allows resolution of fibrotic foci. The regulation of gene expression is intimately linked to chromatin structure. The nucleosome remodeling and deacetylase (NuRD) complex is one of the main regulators for chromatin structure. NuRD has been implicated in a wide variety of nuclear processes including gene transcription, DNA damage repair, maintenance of genome stability and chromatin assembly. On the other hand, previous reports suggest that noncoding RNAs (ncRNAs) are required either for modulating the activity of chromatin regulators or for recruiting them to specific gene loci. Interestingly, even though ncRNAs has been related to IPF, their function at molecular level in IPF has remained elusive. Here, we will investigate the function of micro RNAs (miRNAs) in the nucleus, focusing on the miRNA lethal 7 (Mirlet7, also known as let-7) due to its implication in lung diseases. The present project proposal aims to characterize Mirlet7d-mediated recruitment of NuRD complex to specific loci and fine tuning of its activity during dedifferentiation of activated fibroblasts into resting cells within the context of IPF. We will use as experimental system human primary fibroblasts isolated from donor and IPF patients. Our findings will provide the molecular mechanism as basis for the development of therapeutic approaches against IPF. Furthermore, the therapeutic potential of Mirlet7d against IPF will be confirmed using the bleomycin animal model, the most commonly used model of pulmonary fibrosis. We expect that Mirlet7d administration will attenuate the fibrotic effects induced by bleomycin, thereby confirming our in vitro data and supporting the development of therapeutic strategies against IPF using Mirlet7d.

• DFG Programme: Research Grants