# Metabolic Regulation of Myofibroblast Differentiation

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2023 · $405,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10586076
- **Project number:** 5R01HL151680-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Robert Brian Hamanaka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10586076

## Citation

> US National Institutes of Health, RePORTER application 10586076, Metabolic Regulation of Myofibroblast Differentiation (5R01HL151680-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10586076. Licensed CC0.

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