The role of mTOR signalling in reconfiguring the metabolic network during TGFß-induced myofibroblast differentiation
Professor Rachel Chambers, Centre for Inflammation and Tissue Repair, University College London
Dr. Robert Good, GSK
EARLY START DATE! Join this project from April 2020
Fibrosis is the concluding pathological outcome and major cause of morbidity and mortality in a number of common chronic inflammatory, immune-mediated and metabolic diseases . The progressive and relentless deposition of a collagen-rich matrix is the cornerstone of the fibrotic response and culminates in organ failure and premature death. Epithelial dysfunction is recognised as a key mechanism underlying the development of fibrosis with type II alveolar epithelial cells (AEC2s), the major stem cells of the distal adult lung that maintain lung homeostasis and contribute to epithelial repair, showing an impaired renewal capacity. Despite the rising incidence of fibrotic disease and intense research efforts, there remains a pressing need to develop novel anti-fibrotic therapeutic strategies.
Previous studies from our laboratory underpinned the scientific rationale for progressing the potent PI3K/mTOR inhibitor, Omipalisib, to a first-in-human proof of mechanism trial in patients with idiopathic pulmonary fibrosis (IPF), based on the potential of this compound to interfere with fibroblast function, including TGFβ1-induced collagen deposition [1, 2]. Mechanistic target of rapamycin (mTOR) is a nodal serine/threonine protein kinase which regulates key cellular processes. mTOR forms the catalytic subunit of two complexes, mTORC1 and mTORC2, which are activated by different upstream inputs, elicit different downstream responses, and exhibit differential sensitivity to the allosteric partial mTORC1 inhibitor, rapamycin. We recently reported a key role for mTORC1 in mediating the potent fibrogenic effects of TGFβ1 in primary human lung fibroblasts (pHLFs) and in cancer associated fibroblasts (CAFs) [3, 4]. ATP competitive dual mTOR inhibitors (targeting mTORC1 and mTORC2) are currently in development but the tolerability of long-term dual mTORC1 and mTORC2 inhibition remains unknown. Our recent observation that the TGFβ1-induced collagen response is mediated via the rapamycin-insensitive mTORC1/4E-BP1 axis raises the prospect of developing strategies to selectively inhibit this axis in the context of multiple fibrotic conditions. However, to date, there are no specific mTORC1 inhibitors available so that novel strategies aimed at targeting the mTORC1/4EBP1 axis need to be explored. Unpublished microarray data of laser-captured myofibroblasts from human IPF lung tissue from our laboratory further revealed that the TSC2/Rheb axis, a major upstream regulator of mTORC1 activation formed one of the major cell signalling clusters that correlated with collagen gene expression. Taken together these observations provide human tissue-based evidence for a potential role for Rheb in influencing mTORC1 activation and fibrogenesis in the context of a fibrotic tissue microenvironment.
The overall aim of this project is therefore to perform target validation using genome-editing, genomics and informatics approaches to support the scientific rationale of targeting Rheb as a novel therapeutic approach in the context of fibrosis and the stromal reaction in cancer.
eligibility and application
Applicants must hold, or be expected to achieve, a first or high upper second-class undergraduate honours degree or equivalent (for example BA, BSc, MSci) or a Masters degree in a relevant subject. This project is funded by a 4-year BBSRC studentship, applicants should ensure they have understood the funding eligibility criteria for these studentships. Unfortunately international students are not eligible for programme funding on this project.
For more information regarding the project, please contact Professor Rachel Chambers
Download the APPLICATION GUIDELINES here.