# Glucocorticoid and SGK1 Regulation of CFTR in the Intestine: Role in Diarrhea

> **NIH NIH R56** · YALE UNIVERSITY · 2020 · $417,760

## Abstract

PROJECT SUMMARY
Intestinal fluid secretion is a principal function of enterocytes and is mediated by the cystic fibrosis
transmembrane conductance regulator anion channel, CFTR. Enterotoxins increase CFTR activity and result in
diarrhea, the second leading cause of mortality globally in children under age five. CFTR is also implicated in
diarrhea associated with Irritable Bowel Syndrome (IBS-D), which affects 20% of the US population. In
contrast, impaired fluid secretion resulting from loss of CFTR function is the cardinal feature of cystic fibrosis
(CF). This proposal examines novel mechanisms that regulate CFTR in the intestine with the aim of advancing
our knowledge of gut fluid secretion and developing new therapeutics. We have a special interest in identifying
new and novel druggable targets to treat diarrheal diseases stemming from genetic, infectious and stress-
related etiologies. CFTR is regulated by direct cAMP(PKA) and cGMP(PKG)-dependent phosphorylation and
vesicular traffic in enterocytes. This proposal centers on a key but a previously unrecognized role for
glucocorticoids (GCs) and serum glucocorticoid kinase 1 (SGK1) in regulating intestinal CFTR and the
potential for targeting this pathway to treat diarrhea. SGK1 is transcriptionally regulated by glucocorticoids
(GCs), mineralocorticoids, cell stress, and other factors, and potently regulates ion transport by transcription,
translation, and traffic. However, nothing is known about how GCs and SGK1 regulate CFTR in the intestine.
The hypothesis to be tested here is that GC, SGK1, and kinase signaling pathways regulate CFTR expression,
function, and traffic in the intestine and are therefore important to diarrheal diseases. The hypothesis will be
tested through the following aims: (1) Determine the role of GC and kinase signaling in regulating CFTR
function, mRNA and protein expression in the intestine. (2) Examine the role of GC and kinases in regulating
CFTR membrane traffic in the intestine. (3) Examine the role of SGK1 pathways in diarrheal disease. These
aims will be achieved by employing three animal models (rat, SGK1 KO, and Nedd4-2KO), human jejunum
enteroids (HJE's), cultured cells and scientific approaches including Ussing chamber electrophysiology, in vivo
trafficking assays, shRNA silencing, kinase signaling assays, mass spectrometry, qPCR, immunoblotting and
immunofluorescence staining. Collectively, these studies will break new ground and expand our understanding
of mechanisms regulating CFTR in the intestine and potentially identify novel physiologic targets to treat
CFTR-mediated diarrhea stemming from diverse etiologies.
PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

## Key facts

- **NIH application ID:** 10162075
- **Project number:** 2R56DK077065-11A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Nadia A. Ameen
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $417,760
- **Award type:** 2
- **Project period:** 2008-04-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10162075

## Citation

> US National Institutes of Health, RePORTER application 10162075, Glucocorticoid and SGK1 Regulation of CFTR in the Intestine: Role in Diarrhea (2R56DK077065-11A1). Retrieved via MORVS 2026-10-26 from https://api.morvs.ai/grant/nih/10162075. Licensed CC0.

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