# Mechanisms in the Regulation of SP-A Gene Expression - Renewal - 1 - Resubmission

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $604,905

## Abstract

PROJECT SUMMARY/ABSTRACT
At birth, the alveolar epithelium must mitigate effects of oxidative stress, combat inhaled microorganisms and
modulate the immune environment to protect itself from damaging inflammation. How does this occur? We
postulate that the type II cell serves a crucial role through production of surfactant and immune modulators. In
preterm infants, decreased surfactant and exacerbated inflammation can impair alveolar development and
result in bronchopulmonary dysplasia (BPD), a chronic lung disease with significant morbidity and mortality.
The major surfactant protein, SP-A, an immune modulator, is developmentally upregulated in fetal lung with
type II cell differentiation and surfactant phospholipid synthesis. SP-A expression and type II cell differentiation
in cultured human fetal lung (HFL) epithelial cells are stimulated by cAMP and inhibited by TGF-b and hypoxia.
Mechanisms for O2–dependent induction of type II cell differentiation and SFTPA expression are not fully
understood. Recently, we discovered that the redox-regulated transcription factor, NRF2 and its co-regulated
target genes, C/EBPb and PPARg, were markedly induced by cAMP in HFL type II cells in an O2-dependent
manner. In mouse fetal lung (MFL), a developmental increase in Nrf2, C/ebpb and Pparg, and a decrease in
the Nrf2 inhibitor Keap1 were observed between 14.5 and 19.5 (term) days post-coitum (dpc), with temporal
induction of SP-A and immune modulators, NADH:quinoneoxidoreductase 1 (NQO1), tryptophan 2,3-dioxygen-
ase (TDO2, which catalyzes kynurenine synthesis), and the kynurenine receptor, AhR. Nrf2 KO mice manifest
persistent lung inflammation and exacerbated injury in response to sublethal hyperoxia. Notably, miR-29 family
members, which are induced by Nrf2 and directly target Nrf2 inhibitors Keap1 and TGF-b, are upregulated with
type II cell differentiation. NRF2 binds to response elements in promoters of anti-oxidant and immunomodu-
latory genes. We recently found that NQO1, TDO2, AhR, were upregulated by NRF2 in HFL and MFL epithelial
cells during differentiation in culture. In studies outlined in the following Specific Aims, we will use cultured
human NSCLC adenocarcinoma (adenoCa) cell lines and MFL epithelial cells, wild-type (WT) and gene-
targeted male and female fetal and neonatal mice to test the novel hypothesis that NRF2, acting with C/EBPb
and PPARg, serves a crucial role in fetal and neonatal lung by promoting type II cell differentiation and
enhancing production of key immune modulators that alter the immune cell environment to protect the perinatal
alveolar epithelium from oxidative and inflammatory stress. The following Specific Aims are proposed: (1) use
cultured human adenoCa cells, MFL epithelial cells and miR-29 KO mice to define the regulatory networks of
NRF2, C/EBPβ, PPARg and miR-29, their roles in type II cell differentiation and expression of immune
modulators; (2) analyze effects of a type II cell-specific deletion of Nrf2 in ...

## Key facts

- **NIH application ID:** 9906259
- **Project number:** 5R01HL050022-26
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** CAROLE R MENDELSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $604,905
- **Award type:** 5
- **Project period:** 1993-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906259

## Citation

> US National Institutes of Health, RePORTER application 9906259, Mechanisms in the Regulation of SP-A Gene Expression - Renewal - 1 - Resubmission (5R01HL050022-26). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9906259. Licensed CC0.

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