# Inhibition of an Apical cAMP/cGMP Transporter (MRP4) in the Gut Induces Diarrhea

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2024 · $606,584

## Abstract

Most patients with cystic fibrosis (CF) experience a range of gastrointestinal (GI) complications. Meconium
ileus is present in about 10% of CF newborns. Later in life, the loss or dysfunction of the CF transmembrane
conductance regulator (CFTR) channel activity causes impairment in intestinal fluid secretion and
homeostasis, contributing to the development of constipation, distal intestinal obstruction, and other GI
diseases. In addition to CF patients, chronic constipation affects approximately 2-27% of general population
worldwide; it is one of the most common GI issues in geriatric population. In this proposal, we will address
these two health issues. Based on our previous findings and preliminary data, we hypothesize that (i) the
impairment in intestinal fluid secretion and homeostasis plays a critical role in the pathogenic process of
chronic constipation in CF patients and in geriatric population. (ii) CFTR-MRP4 complexes and the associated
secretory mechanisms are impaired in these two populations. And (iii) the CFTR-MRP4 complexes can be
targeted to restore the impaired secretion and alleviate/cure chronic constipation. Three specific aims were
designed to test our hypothesis: (1) test the regulatory role of CFTR-MRP4 macromolecular complexes in
compartmentalized cAMP/cGMP signaling and in the CFTR-mediated fluid secretion using intestinal stem cells
(ISCs) cultures from CF patients with chronic constipation. (2) test the effects of the current FDA-approved
highly effective CFTR modulator therapies (e.g., Kalydeco® and Trikafta®) and MRP4 inhibitors on intestinal
fluid secretion in enteroids from CF patients with chronic constipation, and study if these two types of
modulators have additive or synergistic effect. And (3) test if the CFTR-dependent fluid secretion in aged
mouse gut is impaired which contributes to chronic constipation and investigate the underlying molecular
mechanism. Our proposal incorporates both conceptual and technical innovations that will not only advance
our understanding of disease pathogenesis of chronic constipation in CF patients and in large ageing
populations, but also help identify possible therapeutic targets for interventions. We will use patient-derived
and clinically relevant samples and adopt a personalized medicine platform: a Bench to Bedside and Back
approach, which warrant a high potential to translate our bench-side findings to clinical disease management.

## Key facts

- **NIH application ID:** 10880061
- **Project number:** 2R01DK080834-17A1
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Anjaparavanda P Naren
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $606,584
- **Award type:** 2
- **Project period:** 2009-08-20 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880061

## Citation

> US National Institutes of Health, RePORTER application 10880061, Inhibition of an Apical cAMP/cGMP Transporter (MRP4) in the Gut Induces Diarrhea (2R01DK080834-17A1). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10880061. Licensed CC0.

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