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Metabolic Regulation of Myofibroblast Differentiation

肌成纤维细胞分化的代谢调节

基本信息

批准号：
10586076
负责人：
Robert Brian Hamanaka
金额：
$ 40.5万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586076
关键词：
3-phosphoglycerate Affect Alleles Amino Acids Biology Carbon Cell secretion Cells Characteristics Cicatrix Collagen DNA Methylation Development Disease Enzymes Epigenetic Process Extracellular Matrix FRAP1 gene Fibroblasts Fibrosis Genetic Genetic Transcription Glucose Glycine Glycolysis Goals Homeostasis Human Impairment In Vitro Knock-in Link LoxP-flanked allele Lung Mediating Metabolic Metabolic Pathway Metabolism Methionine Methylation Modeling Mus Myofibroblast Pathogenesis Pathway interactions Persons Phenotype Play Production Protein Biosynthesis Proteins Pulmonary Fibrosis Reaction Regulation Ribosomal Protein S6 Kinase Role S-Adenosylhomocysteine S-Adenosylmethionine Serine Signal Transduction Testing Therapeutic Transforming Growth Factor beta United States Up-Regulation activating transcription factor activating transcription factor 4 amino acid metabolism cytokine enzyme pathway epigenome epigenomics experimental study fibrogenesis idiopathic pulmonary fibrosis in vivo indium-bleomycin knock-down mTOR Signaling Pathway metabolic abnormality assessment novel overexpression pulmonary function therapeutic target treatment strategy

项目摘要

Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease which has a median survival of 3.5 years and affects approximately 89,000 people in the United States. There is no known genetic cause of IPF, and thus identification of new mechanisms required for disease pathogenesis is of critical importance for the development of novel treatment strategies. A defining feature of IPF is the differentiation of lung fibroblasts into myofibroblasts, which secrete excessive amounts of extracellular matrix (collagen) and are the primary cell responsible for the structural remodeling and impairment of lung function characteristic of IPF. We have recently discovered that myofibroblasts depend on metabolic reprogramming characterized by increased levels of glycolysis and metabolite flux through the de novo serine, glycine, one-carbon (SGOC) pathway to promote glycine production for collagen protein synthesis. Glycine constitutes one third of all amino acids in collagen protein and de novo synthesis of glycine from glucose is required to support collagen protein synthesis by myofibroblasts. However, the signaling and transcriptional regulators of this metabolic reprogramming in fibroblasts are unknown. The central goal of this proposal is to identify the regulators of metabolic reprogramming in myofibroblasts and to determine their role in lung fibrosis. The premise underlying this goal is that elucidating the mechanisms of metabolic regulation in myofibroblasts will unveil new strategies to fulfill the sorely unmet therapeutic need in IPF. Our preliminary results show that TGF-β (Transforming Growth Factor-β, the key cytokine involved in fibrosis), promotes signaling through the mTOR pathway, which activates ATF4 (activating transcription factor 4). ATF4 is required for the expression of SGOC pathway enzymes in myofibroblasts. We further show that SGOC pathway activation not only promotes collagen protein production by myofibroblasts, but alters the epigenome of these cells, possibly providing additional ways to target myofibroblast biology for therapeutic purposes. In the current proposal, we aim to determine the regulators of myofibroblast metabolism and determine the mechanisms by which altered metabolism contributes to the myofibroblastic phenotype. In Specific Aim 1 we will determine how the transcription factor ATF4 regulates the SGOC and other metabolic pathways in lung fibroblasts in vitro and in vivo. In Specific Aim 2, we will determine how the mTOR signaling pathway regulates ATF4 and other transcriptional regulators of cellular metabolism in lung fibroblasts in vitro and in vivo. In Specific Aim 3, we will determine how SGOC pathway activation contributes to epigenetic changes in lung fibroblasts in vitro and in vivo. Our proposed experiments will identify and fully characterize multiple targetable pathways required for fibrogenesis.

特发性肺纤维化（IPF）是一种致命疾病，中位生存期为3.5年