# Caraballo Diversity Supplement 093019

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $113,853

## Abstract

PROJECT SUMMARY/ABSTRACT
In this MPI RO1 application, we show that high endoplasmic reticulum (ER) stress and dysregulated unfolded
protein response (UPR) signaling in lungs precedes development of fibrosis in murine models of pulmonary
fibrosis (PF)—similar changes have been reported in lungs of human patients with idiopathic pulmonary
fibrosis (IPF). We find that the pathognomonic features of these changes are due to hyperactive signaling by
IRE1α, an ER transmembrane protein containing bifunctional kinase/endoribonuclease (RNase) catalytic
activities. We have found that novel, small molecule UPR kinase inhibitors of IRE1α, called KIRAs (an acronym
for kinase-inhibiting RNase attenuators) reduce IRE1α's destructive UPR signaling and show potent anti-
fibrotic effects in ER-stressed lungs of mice. Thus, even as IRE1α emerges as a potential therapeutic target for
treating human patients suffering from IPF, the underlying mechanistic basis for the cytoprotective, anti-fibrotic,
efficacy of the KIRA compounds needs to be understood. Through this application, we propose to understand
the basis of the KIRA-mediated salutary effects on reducing lung epithelial injury, dysregulation, and death,
and also on reducing collagen overproduction by activated fibroblasts. The project is enabled by the
complementary skill sets of two labs (Papa and Sheppard) that together have found the UPR is wired through
a signaling loop that leads to classical TGF-β-induced, pro-fibrotic signaling in lungs. Thus, the mechanistic
understanding to be gained from the successful completion of the proposed studies promises to reveal new
nodes and targets for rational disease modification in idiopathic pulmonary fibrosis, a currently incurable
disease.

## Key facts

- **NIH application ID:** 10026554
- **Project number:** 3R01HL145037-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Feroz R Papa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $113,853
- **Award type:** 3
- **Project period:** 2019-02-01 → 2020-09-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026554

## Citation

> US National Institutes of Health, RePORTER application 10026554, Caraballo Diversity Supplement 093019 (3R01HL145037-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10026554. Licensed CC0.

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