# Sineoculis Homeobox Homolog 1 (Six1) in Pulmonary Fibrosis

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $534,212

## Abstract

Project Summary
One of the most widespread presentations of Interstitial Lung Disease is Idiopathic Pulmonary Fibrosis (IPF), a
chronic, progressive and fatal disease. The prevalence of IPF in the US has increased 2-fold in the last 10 years
and it affects ~180,000 Americans. Subclinical epithelial injury has been identified as a central process in IPF.
The prognosis of IPF is dire, with a median survival of 3.8 years among adults 65 years or older. Important
advances in the therapy of IPF include the approval of nintedanib and pirfenidone. Although these agents are
able to clinically attenuate the loss of lung function in IPF, they do not completely halt or reverse the progression
of disease. This underscores the need to identify novel therapies for the treatment of IPF. Epithelial reprograming
of alveolar type II cells (AEC2) is a central process that leads to lung remodeling in IPF. Intriguingly, we have
identified a novel developmental transcription factors that is up-regulated in IPF: Sine Oculis Homeobox Homolog
1 (SIX) and its co-factors eyes absent (EYA)-1 and 2. Using an experimental model of bleomycin (BLM)-induced
lung fibrosis, we demonstrate that deletion of SIX1 in AEC2 inhibited the development of lung fibrosis and
improved lung function and that SIX1 overexpression in AEC2 results in an atypical lung epithelization. Taken
together these results point at elevated SIX1 in AEC2 as an important pathway for lung fibrosis. Preliminary data
suggests that activation of this pathway promotes expression of senescent associate secretory phenotype
(SASP) factors and hyperplasia of AEC2, key features of lung fibrosis. However, the SIX1/EYA driven
mechanisms that promote these changes are not fully understood and will be interrogated in this proposal.

## Key facts

- **NIH application ID:** 10181872
- **Project number:** 1R01HL157100-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Harry Karmouty-Quintana
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $534,212
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10181872

## Citation

> US National Institutes of Health, RePORTER application 10181872, Sineoculis Homeobox Homolog 1 (Six1) in Pulmonary Fibrosis (1R01HL157100-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10181872. Licensed CC0.

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