# Cholinergic hyperinnernation in early life regulates long-term airway reactivity

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $171,990

## Abstract

Project Summary:
 Asthma is a chronic respiratory disease affecting more than 25 million people including 7 million children
in the United States and imposing a substantial health and economic burden on patients, their families and the
communities. Although asthma may affect all age groups, it most often starts during childhood. Clinical
observations have revealed early life environmental insults are associated with increased risk of chronic airway
obstructive diseases including asthma. In addition, there is increasing recognition that lung function throughout
life is profoundly impacted by respiratory events that occur during the time period of postnatal lung development.
These findings highlight the significance of more fully understanding age-related specific airway adaptive
changes from environmental exposures in early life.
 Our work in progress with an early life mouse asthma model has revealed a key role of neural
dysregulation of airway smooth muscle (ASM) in the maintenance of airway hyperreactivity (AHR). We found
early life allergen exposure induced a unique upregulation of ASM contractility via cholinergic hyperinnervation.
This contractile plasticity of ASM in the time window of postnatal airway development played a key role in
retaining long term AHR. In contrast, alteration in neural regulation and subsequent long term enhancement of
airway contractility was not seen in a murine model of adult asthma. Moreover, microarray analysis of ASM
revealed gene expression of CD38 and -actinin1 (ACTN1) was selectively upregulated in P21 ASM following
allergen exposure. These genes have established role in the contractile regulation of ASM. We therefore
hypothesize that cholinergic stimulation during postnatal development aberrantly activates Ca2+ and ACTN1-
mediated pathways in ASM, which in turn causes persistent AHR. We propose to test this hypothesis by 1)
identifying the critical time window during which ASM is vulnerable to the aberrant cholinergic regulation; 2)
investigating two potential mechanisms underlying cholinergic stimulation induced ASM hypercontractility, ie
CD38 mediated Ca2+ signaling pathway and ACTN1 mediated intracellular mechanotransduction; and 3)
evaluating the efficacy of anti-cholinergic medication in the prevention of persistent AHR following early life
allergen exposure.
 With the guidance of my mentors, Drs. Xingbin Ai and Bruce Levy, we have developed a five-year training
program that includes both tailored didactic and technical training to develop additional skills for study of the
regulation of ASM in health and disease. Importantly, this project will be overseen by a scientific career advisory
committee with expertise related to key areas of this proposal, including ASM physiology, molecular and
developmental lung biology and animal disease models. The proposed career development plan will establish
scientific foundations and provide the additional training necessary to achieve my ultimate goal of becoming ...

## Key facts

- **NIH application ID:** 10217685
- **Project number:** 7K08HL135443-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Yan Bai
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $171,990
- **Award type:** 7
- **Project period:** 2017-07-14 → 2023-12-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217685

## Citation

> US National Institutes of Health, RePORTER application 10217685, Cholinergic hyperinnernation in early life regulates long-term airway reactivity (7K08HL135443-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10217685. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*