# Program to promote lung regeneration and block fibrosis

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $968,976

## Abstract

ABSTRACT
The goal of this research program is to understand the interactions between lung epithelial and mesenchymal
cells in sufficient detail to deliver new therapeutic interventions in pulmonary fibrosis, a process without disease
modifying therapies. This program is anchored by a recently funded RO1 to further elucidate mechanisms of a
fibroblast-specific trihydroxyphenolic inhibitor of LOXL2 and TGFR1 with potent in vivo anti-fibrotic effects. We
will test one of these, EGCG, in a proof of principle clinical trial. Unpublished data show reversal of a core set
of pro-fibrotic tissue biomarkers in IPF patients given EGCG two weeks prior to diagnostic lung biopsy. The
R35 mechanism allows us to integrate our capacity to attenuate fibrosis with the broader issue of defective
epithelial regeneration in IPF, a competing process with fibrogenesis. This is sometimes simplified in the idea
repeated epithelial injury leads to stem cell failure thereby creating an unrelenting pro-fibrotic environment. But
the lung is resilient with multiple, spatially distinct progenitor cells whose identify and integrative functions
remain poorly understood, especially in IPF patients. This paradigm also overlooks the potentially critical
contribution of pro-fibrotic mesenchymal cells in driving further loss of the epithelium. Type II cells in the IPF
lung at the time of lung transplant are less than 15% of that present in a normal lung. The program will focus
on further elucidating the potential of resident epithelial stem/progenitors in mouse and human to regenerate
alveolar integrity. In parallel, mechanisms by which activated mesenchymal cells contribute to dysfunction and
loss of these epithelial progenitors will be defined. We plan to leverage fibroblast-specific TGFb1 inhibition to
study its impact on progenitor cells in both animal models and in IPF patients, for example by single cell RNA-
seq of tissues from untreated and EGCG treated patients. We envision a future small molecule image-based
screen to identify agents that improve type II cell health in cultured epithelial/fibroblast organoids. Overall the
R35 program gives us the opportunity to integrate all of these directions into a centrally themed,
multidimensional approach that should transform how we view lung regeneration and fibrogenesis and how we
treat patients with unrelenting fibrosis.

## Key facts

- **NIH application ID:** 10107866
- **Project number:** 5R35HL150767-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Harold A Chapman
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $968,976
- **Award type:** 5
- **Project period:** 2020-02-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107866

## Citation

> US National Institutes of Health, RePORTER application 10107866, Program to promote lung regeneration and block fibrosis (5R35HL150767-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10107866. Licensed CC0.

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