# Development of PNEC innervation and neuroplasticity after early life insult

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $427,701

## Abstract

ABSTRACT
How pulmonary neuroendocrine cells (PNECs) become innervated and to what extent nerves regulate PNEC
function in development and diseases are open and basic questions for the field. The objective of this
proposal is to address these fundamental issues and to assess the key role of neurotrophin 4 (NT4) in these
events. Using a NT4-/- mouse line and a neonatal mouse model of allergen exposure, we generated
preliminary data leading to 3 hypotheses that will be studied in this proposal: 1) NT4 is required for PNEC
innervation during development and for the increases in PNEC innervation following early life insults; 2) early
life allergen exposure alters the function of sensory afferents and efferent nerves that innervate PNECs
thereby causing deregulated γ-aminobutyric acid (GABA) secretion and long-term goblet cell metaplasia; 3)
pulmonary mast cells are a candidate source of elevated NT4 levels following early life allergen exposure. To
summarize, we found that NT4 was expressed by PNECs during postnatal development and acted as a trophic
factor for the innervating nerves to establish connection. Allergen exposure to developing, postnatal lungs
aberrantly elevated the levels of NT4. Under this pathological condition, we discovered that PNEC innervation
was increased associated with prolonged goblet cell metaplasia. Notably, PNECs were the only cell source of
GABA in lungs, a signal essential for allergen-induced goblet cell metaplasia in mouse models and associated
with mucous overproduction in human asthmatics and smokers. In addition, NT4 was required for PNEC
hyperinnervation and deregulated GABA secretion, consistent with the established paradigm in other
neuroendocrine systems that nerves regulate endocrine secretion. These preliminary findings point to an
essential role for NT4 in PNEC innervation during development and neuroplasticity following early life injury,
which will be extensively characterized by comparing the pattern and degree of PNEC innervation between
wild type and NT4-/- mice with and without allergen exposure using markers for different types of nerves (Aim
1). To connect NT4-induced PNEC hyperinnervation to prolonged goblet cell metaplasia following early life
allergen exposure, proposed experiments in Aim 2 will assess functional changes in sensory afferents and
efferent signals that induce GABA secretion from PNECs and their relationships to NT4. Lastly, given the
central role of NT4 in aberrant PNEC innervation under pathological conditions, we examined NT4 expression
in injured lungs. We found an enlarged, activated mast cell population expresses NT4 during early life allergen
exposure. Whether pulmonary mast cells contribute to PNEC hyperinnervation by producing NT4 will be
evaluated (Aim 3). To further enhance disease relevance, we will validate key findings from the mouse work in
infant primate models of injury and human lung samples. Together, this proposal investigates complex
interactions between nerves, P...

## Key facts

- **NIH application ID:** 10089028
- **Project number:** 7R01HL132991-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Xingbin Ai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $427,701
- **Award type:** 7
- **Project period:** 2017-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10089028

## Citation

> US National Institutes of Health, RePORTER application 10089028, Development of PNEC innervation and neuroplasticity after early life insult (7R01HL132991-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10089028. Licensed CC0.

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