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

纤维化是许多慢性炎症和代谢性疾病的病理特征[1]。在所有纤维化疾病中进展最快、最致命的是特发性肺纤维化(IPF)，其治疗策略有限[2]。纤维化疾病的病理特征是细胞外基质(ECM)的过度产生和沉积，最终会干扰正常的器官功能，导致过早死亡。肌成纤维细胞是纤维化反应的关键效应细胞，负责细胞外基质的产生和沉积[3]。肌成纤维细胞可以从成纤维细胞分化而来，这种分化是由细胞因子TGFB1[4]促进的。TGFB1/mTOR信号轴包含关键的mTOR蛋白复合体mTORC1，已被证明在纤维化形成中起关键作用。最近来自Chambers小组的数据显示，mTORC1在TGFB1诱导的胶原合成(胶原是ECM的关键成分)中起关键作用，作用于下游底物4e-BP1，一种翻译抑制蛋白[5]。此外，最近对CRISPR/Cas9 mTORC1基因敲除进行的RNAseq分析表明，该蛋白复合体调控肌成纤维细胞中TGFB1介导的一些翻译途径，但不调控成纤维细胞中TGFB1介导的翻译途径，包括真核细胞的翻译起始、延伸和终止，以及帽子依赖的翻译起始。该项目的一个关键目标是通过测量TGFB1调节的翻译组来确定参与纤维化反应的mTORC1下游底物。长期目标是在TGFB1/mTOR信号级联中确定潜在的新治疗靶点，并进一步加深我们对纤维化的理解。

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.