# Mechanism of Prostone Activation During CFTR Modulation

> **NIH NIH R56** · NATIONAL JEWISH HEALTH · 2022 · $426,793

## Abstract

PROJECT SUMMARY/ABSTRACT
Cystic fibrosis (CF) is an autosomal recessive disease resulting from mutations in the CF transmembrane
conductance regulator (CFTR) gene that disrupts the functions of CFTR. Approximately 90% of people with CF
have at least one copy of F508del CFTR. F508del CFTR function can be repaired to a significant extent by
double and triple combination medications on the market in the USA. The other 10% of people with CF do not
have F508del and many of their mutations do not have a medication to restore CFTR. The GOAL of this grant
is to explore the efficacy of a new class of CFTR modulator—a prostone—for the ability to activate wild-type and
mutant CFTR. Our HYPOTHESIS is that lubiprostone and related prostones activate many forms of CFTR—
normal CFTR, F508del CFTR, or other rare mutations, especially those that have been rescued to the cell
surface by the marketed modulators. The prostones were developed as chloride channel 2 (CLCN2) activators
but interact with receptor-mediated pathways present in airway and gastrointestinal epithelia to boost CFTR-
mediated chloride secretion. It is likely that select prostones are dual modulators of both CFTR and CLCN2.
CFTR-mediated chloride transport is a meaningful and quantifiable measure to assess efficacy of channel
correctors, activators, potentiators, and amplifiers. Correctors, stabilizers, and amplifiers function by increasing
CFTR protein levels on the cellular surface, and potentiators increase the open probability of the CFTR channel
to increase anion permeability. Current activators that raise cAMP in vitro, forskolin and IBMX, are not clinically
safe or available, which means that the double and triple combination modulators on the market are relying on
endogenous levels of cAMP. Specific Aim 1: To quantify the effects of lubiprostone and other novel CFTR
activators on ion transport in non-CF, F508del CFTR, and non-F508del mutant CFTR-expressing airway
epithelial cell cultures. Aim 1A tests the hypothesis that acute lubiprostone stimulates CFTR-mediated chloride
transport. Aim 1B tests the hypothesis that chronic exposure to CFTR activators recruits CFTR function and can
stimulate CLCN2-mediated chloride secretion. Aim 1C tests the hypothesis that increased CFTR function leads
to increased airway surface liquid depth. Specific Aim 2: To study the PGE2 signaling pathway during activation
with lubiprostone. The hypothesis is that one or more EP receptor subtypes are target(s) of lubiprostone during
activation of chloride secretion by wild-type and mutant CFTR. Aim 2A addresses GPCR coupling from
lubiprostone to CFTR and differentiates from lubiprostone activation of CLCN2. Aim 2B tests the hypothesis that
EP2 and EP4 receptors are expressed in the same cells as CFTR.

## Key facts

- **NIH application ID:** 10687435
- **Project number:** 1R56HL157318-01A1
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Pamela L. Zeitlin
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $426,793
- **Award type:** 1
- **Project period:** 2022-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10687435

## Citation

> US National Institutes of Health, RePORTER application 10687435, Mechanism of Prostone Activation During CFTR Modulation (1R56HL157318-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10687435. Licensed CC0.

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