# Chemical Biology of CFTR Regulation

> **NIH NIH F32** · UNIVERSITY OF IOWA · 2020 · $69,306

## Abstract

SUMMARY
Mutations that render the cystic fibrosis transmembrane conductance regulator (CFTR) defective in function
lead to cystic fibrosis, a devastating multisystem disease affecting tens of thousands of people worldwide.
Drug discovery efforts by Vertex, Inc. (Cambridge, Mass. USA) have yielded clinically efficacious drug
combinations, establishing CFTR as a therapeutically accessible target. Thus far all of the successfully tested
therapies include Ivacaftor, which as a “potentiator,” rather than an activator of CFTR relies at least to some
degree on the phosphorylation state of CFTR, which is subject to dynamic hormonal regulation in vivo. In
addition, accumulating evidence suggests that Ivacaftor works through an ATP-independent mechanism,
meaning that the canonical route by which stable CFTR openings are achieved, namely ATP-driven
dimerization of the intracellular binding domains, is not exploited by Ivacaftor. By aiming to better understand
both phospho regulation and ATP binding in CFTR, the two aims of this proposal are expected to support
future efforts to develop mechanism-based therapies that increase CFTR function. Two scientific aims in my
proposal describe the means to achieve these goals. The first of these aims will use a powerful method we
have developed whereby the phosphorylation state of a specific site in the CFTR channel is controlled by a
brief (<1 second) flash of light. This will allow me to observe the intrinsic phosphorylation rates of the channel,
and the functional consequence, in real time, in a cellular environment. Given that phosphoregulation of ion
channels is well-described in the lung and heart, and often defective in cardiovascular disease, this training
and the anticipated ensuing discoveries will likely lead directly to additional opportunities on other ion channel
proteins with ties to human health. The second aim will examine the interaction chemistry that is utilized
between nucleotide binding domains (NBD) and ATP, their regulatory target. NBDs are ancient domains
(billions of years old) that are found throughout biology, thus advancing their mode of action will simultaneously
impact multiple areas. I will use structural biology and advanced spectroscopic methods to examine the
mechanism of how the soluble NBDs from the CFTR channel bind to their regulatory target, ATP. The likely
common output from these combined efforts will be the publication of multiple high value papers and the
advanced training in modern techniques for the study of ion channel proteins. Additionally, CFTR’s evolution
allows it to serve as a model for both phospho-regulation of ion channels (in common with many other clinically
relevant channels in the lung and heart) and for ATP-based activation of other ABC transporters which play
important roles in lung physiology. Accordingly, execution of this proposal will establish a platform to ask
similarly important questions relating to the regulation of other membrane proteins. As a tr...

## Key facts

- **NIH application ID:** 10001337
- **Project number:** 5F32HL149184-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Daniel T Infield
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,306
- **Award type:** 5
- **Project period:** 2019-07-22 → 2021-07-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001337

## Citation

> US National Institutes of Health, RePORTER application 10001337, Chemical Biology of CFTR Regulation (5F32HL149184-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001337. Licensed CC0.

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