# Kisspeptins in the Airway

> **NIH NIH R01** · NORTH DAKOTA STATE UNIVERSITY · 2021 · $144,816

## Abstract

Airway smooth muscle (ASM) is a key cell type in asthma, contributing to airway hyperreactivity (AHR) and
remodeling (proliferation, fibrosis). Asthma is more prominent in women and multiple studies highlight a role for
sex hormone effects on ASM. However, it is unclear whether sex hormones are protective or detrimental, given
observations of enhanced inflammation vs. promotion of bronchodilation.
These uncertainties led us to consider
if mechanisms upstream or even independent of sex hormones play a role, or alternatively, if asthma involves
loss of intrinsic protective mechanisms. Drawing upon data in CNS, particularly in puberty which associates with
more asthma in women, and preliminary data, we propose that the gonadotrophin regulators kisspeptins (Kp)
and their receptor (KISS1R) serve a normally protective, anti-remodeling role when locally expressed in airways.
We further propose that inflammation/asthma and estrogens compromise Kp/KISS1R roles.
There is currently
no information on Kp/ KISS1R in airways and/or in asthma, but potential relevance lies in the fact that Kp
signaling can regulate proliferation, migration and signaling elements also important for ASM remodeling and
contractility.
Preliminary studies show human ASM from females have less Kp and KISS1R compared to males,
further reduced during asthma/inflammation. In addition, physiological levels of 17-β-estradiol (E2) reduce Kp in
ASM. Functionally, Kp via KISS1R downregulates ASM proliferation and remodeling and reduces ASM [Ca2+]i.
In a mixed allergen mouse model of asthma, Kp agonist (metastin) improved lung resistance and compliance.
Our overall hypothesis is that ASM-derived Kp signaling has a protective role lost in inflammation and asthma,
permitting AHR and remodeling. Our proposed studies will define the role of Kp and KISS1R in asthma via three
Aims: Aim 1: Determine mechanisms by which inflammation and E2 regulate Kp/KISS1R in human ASM in the
context of asthma. Aim 2: Determine mechanisms by which Kp/KISS1R signaling influences ASM structure and
function in the context of asthma. Aim 3: In a mouse model of allergic asthma, determine role of Kp/KISS1R in
AHR and remodeling. Using human ASM cells and tissues of male vs. female (asthmatics vs. non-asthmatics),
Aim 1 explores the idea that asthma and inflammation or E2 decrease expression of Kp and KISS1R. Aim 2
explores Kp/KISS1R-based signaling in human ASM proliferation, migration, ECM production, and autocrine role
of ASM-derived Kp, further exploring interactions with inflammatory cytokines or E2. We will also explore if
Kp/KISS1R is important for Ca2+/contractility. Aim 3 applies a mixed allergen model of asthma to WT and KISS1R
KO mice to study importance of Kp (metastin vs. KISS1R inhibitor). Ovariectomy (OVX) is used to distinguish E2
from Kp effects. Changes in airway contractility are assessed using FlexiVent and precision cut lung slices, and
structural and molecular changes in ASM assessed by laser capture m...

## Key facts

- **NIH application ID:** 10464150
- **Project number:** 3R01HL146705-02S1
- **Recipient organization:** NORTH DAKOTA STATE UNIVERSITY
- **Principal Investigator:** Sathish Venkatachalem
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $144,816
- **Award type:** 3
- **Project period:** 2020-03-05 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464150

## Citation

> US National Institutes of Health, RePORTER application 10464150, Kisspeptins in the Airway (3R01HL146705-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464150. Licensed CC0.

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