Elucidation of the role of mTORC1 in influencing TGFB1-modulated regulation of the fibrotic response

点击翻译按钮获取中文摘要

Fibrosis is a pathological feature of many chronic inflammatory and metabolic diseases[1]. The most rapidly progressive and fatal of all fibrotic conditions is idiopathic pulmonary fibrosis (IPF), for which there are limited therapeutic strategies available [2]. Fibrotic diseases are pathologically characterised by excessive production and deposition of extracellular matrix (ECM), which can ultimately interfere with normal organ function and lead to premature death. Myofibroblasts are the key effector cells of the fibrotic response and are responsible for the production and deposition of ECM [3]. Myofibroblasts can be derived from fibroblasts, and this differentiation is promoted by the cytokine TGFB1 [4]. The TGFB1/mTOR signaling axis contains the key mTOR protein complex mTORC1, which has been shown to be critical for fibrogenesis. Data from the Chambers group recently showed that mTORC1 is crucial for TGFB1-induced collagen synthesis (collagen is a crucial component of the ECM) acting via the downstreamsubstrate 4E-BP1, a translation repressor protein [5]. In addition, recent RNAseq analyses carried out on CRISPR/Cas9 mTORC1 knockouts showed that the protein complex regulates a number of TGFB1-mediated translation pathways in myofibroblasts but not fibroblasts, including eukaryotic translation initiation, elongation and termination, as well as cap-dependent translation initiation. A key aim of this project is to identify mTORC1 downstream substrates involved in the fibrotic response by measuring the TGFB1-regulated translatome. The long-term goal is to identify potential novel therapeutic targets within the TGFB1/mTOR signalling cascade and further our understanding of fibrosis.