# Beyond the Barrier: Alveolar Epithelial Cell Biology in Health and Disease

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $948,000

## Abstract

Originally regarded as a simple barrier against passive leakage of fluid into lung airspaces critical for gas
exchange, the alveolar epithelium is now viewed as a key regulator of alveolar homeostasis. Furthermore,
alterations in alveolar epithelium are central to the pathogenesis of a number of diseases impacting respiratory
health including idiopathic pulmonary fibrosis (IPF) and emphysema, making it important to understand
mechanisms responsible for its normal maintenance and repair following injury. My research program is
thematically focused on alveolar epithelial cell (AEC) plasticity/‘reprogramming’, with the overall goal of
characterizing the molecular basis of AEC function and phenotype in order to elucidate mechanisms leading to
aberrant repair and develop strategies for improving outcome following injury, consistent with the mission of
NHLBI. Our work to date has contributed to new paradigms in AEC biology, including demonstration of an
active role for alveolar epithelial type I (AT1) cells in alveolar homeostasis, AEC plasticity, a central role for
alveolar epithelium in pulmonary fibrosis, discovery of a novel role of tight junctions (TJ) in regulation of lung
stem/progenitor cell homeostasis, and elucidation of key pathways regulating AEC differentiation. Building on
this work, we will focus going forward on complementary areas of 1) regulation of normal AEC
phenotype/differentiation, 2) role of AEC in lung fibrosis and 3) regulation of endogenous lung stem/progenitor
cell homeostasis coordinated by interactions with TJ, in order to address key gaps in our understanding of
normal AEC progenitor potential/differentiation and disruption in disease. Success will be ensured by a)
synergistic interactions among a strong team with expertise in AEC differentiation, lung development,
epigenetics/bioinformatics and regenerative medicine and b) use of innovative models (e.g., induced
pluripotent cells (iPSC) from normal and IPF patients) to investigate AEC differentiation in health and disease.
Application of genome-wide genomic and high-throughput technologies will provide potentially transformative
insights into previously unexplored cell-specific epigenetic (especially histone) modifications regulating normal
and aberrant differentiation of normal and IPF AEC. Novel insights regarding regulation of lung stem/progenitor
function by intracellular transduction of signals from TJ have the potential to be harnessed to augment lung
regeneration after injury. Deliverables with broad application to the lung research community include improved
methods for AT1 cell isolation, novel AT1 cell markers/Cre lines, and genome-wide datasets to be deposited as
a shared resource. Our integrated team approach using primary (including human) AEC, spheroid cultures and
iPSC, together with genome-wide transcriptomic/epigenomic analyses and disease modelling, to address
critical questions related to AEC maintenance and repair has significant translational potenti...

## Key facts

- **NIH application ID:** 10403364
- **Project number:** 7R35HL135747-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Zea Borok
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $948,000
- **Award type:** 7
- **Project period:** 2021-08-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10403364

## Citation

> US National Institutes of Health, RePORTER application 10403364, Beyond the Barrier: Alveolar Epithelial Cell Biology in Health and Disease (7R35HL135747-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10403364. Licensed CC0.

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