# Defining molecular signals that influence airway basal cell renewal and growth

> **NIH NIH F31** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $46,752

## Abstract

PROJECT SUMMARY
Basal cells (BCs) of mammalian airways are resident stem cells of the pseudostratified epithelium of the airways
and understanding how they are regulated and maintained will be important for understanding their aberrant
growth in disease, such as COPD, cystic fibrosis and cancer, as well as for developing novel methods for
harnessing BCs for the purposes of regenerative medicine. The Hippo signaling pathway has emerged as an
important regulator of BC growth. Hippo signaling controls the activity of the transcriptional regulators YAP and
TAZ (YAP/TAZ) by restricting nuclear YAP/TAZ localization in mature differentiated airway cells. Nuclear YAP
activity has been shown to promote BC growth in the airways and has been shown to play important roles in a
variety of stem cell populations in other tissues and organs. YAP is implicated in maintaining the airway BC fate
through direct association with the basal cell specific transcription factor, p63. Airway basal stem cells play
important roles lung injury repair, but the signals that regulate their growth and self-renewal are poorly
understood. Our studies, as well as others, indicate that the nuclear activity of the transcriptional regulator YAP
plays important roles in airway basal cell growth and in this proposal, we aim to understand the roles and
regulation of YAP activity in this context. In this proposal we aim to use genetic mouse models which contain
conditional knockouts of Hippo pathway regulating kinases, LATS1 and LATS2, in airway basal cells to
understand how Hippo inactivity and subsequent YAP nuclear activity influences BC maintenance through its
interaction with p63. Our preliminary data suggest that LATS1/2 deletion in Krt5 positive basal cells leads to
basal cell hyperplasia and the formation of distinct populations of basal cells. Those adjacent to the basement
membrane have the highest levels of nuclear p63, whereby this expression is reduced or lost in the Krt5+ cells
that are more luminal in the hyperplastic lesion. Our studies further suggest that YAP activity in BCs is influenced
by signals, such as FGF10, that come from stromal cells in the basement membrane, and we hypothesize that
these signals influence YAP interactions with p63 to guide a BC self-renewal transcriptional program. We aim
to unveil novel biochemical pathways that describe how signals from the basement membrane are transduced
through BC receptor tyrosine kinases to increase YAP-p63 functional activity and BC self-renewal and growth.
Specifically, we propose: 1) to determine if LATS1/2-depletion and subsequent YAP activation in airway basal
cells influences BC maintenance through YAP-p63 interactions; 2) how signals from the basement membrane
may promote these YAP/p63 interactions; and 3) if YAP-p63 complexes differentially regulate gene expression
to promote BC fate. Ultimately this study will offer molecular insight into how BC self-renewal and expansion is
regulated, which may offer directions...

## Key facts

- **NIH application ID:** 10321667
- **Project number:** 5F31HL149381-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Adeline Marie Matschulat
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10321667

## Citation

> US National Institutes of Health, RePORTER application 10321667, Defining molecular signals that influence airway basal cell renewal and growth (5F31HL149381-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10321667. Licensed CC0.

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