# Illuminating the role of chloride channel regulator CLCA4 in TMEM16 Family potentiation and disease

> **NIH NIH R03** · WASHINGTON UNIVERSITY · 2021 · $157,500

## Abstract

ABSTRACT:
 The calcium-activated chloride channel regulator CLCA4 has been associated with and suggested as a
drug target for inflammatory diseases of the airway and gastrointestinal tract including asthma, COPD, cystic
fibrosis, infectious diarrhea, Crohn's disease, ulcerative colitis, and some cancers. However, a detailed
understanding of its biological functions has lagged far behind its association with these diseases, largely due
to complete lack of biochemical knowledge and quality antibody reagents. We recently made groundbreaking
advances investigating a related family member, CLCA1, by showing that it is a self-cleaving metalloprotease
that binds to and potentiates the calcium activated chloride channel TMEM16A. In our preliminary data we
show that CLCA4 acts in a similar manner on another distinct TMEM16 family member, TMEM16B. Therefore,
we are uniquely poised to generate significant advances in our understanding of CLCA4 function in health and
disease. This pilot project will develop the knowledge base and tools required to facilitate this. In Aim 1, we will
investigate the mechanism of regulation of CLCA4 activity and comprehensively validate that TMEM16B is the
sole TMEM16 family member modulated by CLCA4. In Aim 2, we will develop a novel panel of monoclonal
antibody reagents specific for the mature, cleaved forms of CLCA4 (N-CLCA4 and C-CLCA4) that can be used
in several experimental formats, and carry out initial analysis of healthy and diseased airway and intestinal
tissue and biological samples with them. The long-term goal of this project (beyond this pilot R03) is to develop
a comprehensive mechanistic understanding of CLCA4 function in health and disease, which we believe is
sorely underappreciated. Successful completion of this pilot will provide the knowledge and tools to investigate
the functional roles of CLCA4 in specific diseases and to develop targeted therapeutics in subsequent projects.

## Key facts

- **NIH application ID:** 10217542
- **Project number:** 1R03TR003673-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** THOMAS John BRETT
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $157,500
- **Award type:** 1
- **Project period:** 2021-05-15 → 2023-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217542

## Citation

> US National Institutes of Health, RePORTER application 10217542, Illuminating the role of chloride channel regulator CLCA4 in TMEM16 Family potentiation and disease (1R03TR003673-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10217542. Licensed CC0.

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