# Determining the Physiological Mechanism of CFTR Inhibition by Sphingomyelinase

> **NIH NIH F31** · EMORY UNIVERSITY · 2020 · $43,890

## Abstract

PROJECT SUMMARY
The research proposed in this application seeks to address the physiological basis of inhibition of the Cystic
Fibrosis Transmembrane conductance Regulator (CFTR) by the enzyme sphingomyelinase (SMase). CFTR is
the protein defective in the common genetic disease Cystic Fibrosis (CF). The current major cause of death for
CF is pulmonary insufficiency caused by frequent bacterial infections and persistent inflammation of the lungs.
Interestingly, both infection and inflammation promote secretion of the enzyme SMase, which our lab has shown
to decrease the function of CFTR. To understand if SMase plays a role in worsening disease severity in CF, we
will first quantify the amount of SMase in CF lungs by using mass spectrometry and immunohistochemistry. We
will then determine the mechanism by which SMase inhibits CFTR by using electrophysiology to study the
behavior of CFTR and pharmacological methods to negate the effects of SMase on CFTR activity. Lastly, we
will determine the effect SMase-mediated inhibition of CFTR has on the efficacy of the only clinically-approved
CFTR potentiator drug (VX-770). Based on our previous findings, we hypothesize that SMase is upregulated in
the CF lung, inhibits CFTR via a novel mechanism, and prevents VX-770 from rescuing CFTR activity. Together,
these data will help determine if CF patients need co-administration of a drug to nullify the effects of SMase on
CFTR.

## Key facts

- **NIH application ID:** 10000994
- **Project number:** 5F31HL143863-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Kirsten Alyssa Cottrill
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $43,890
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-08-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000994

## Citation

> US National Institutes of Health, RePORTER application 10000994, Determining the Physiological Mechanism of CFTR Inhibition by Sphingomyelinase (5F31HL143863-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10000994. Licensed CC0.

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