Elucidation of the role of mTORC1 in influencing TGFB1-modulated regulation of the fibrotic response
Lead Research Organisation:
University College London
Department Name: Medicine
Abstract
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 downstream
substrate 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.
[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 downstream
substrate 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.
