# The Role of KCNMB1 and the Large Conductance Potassium (BK) Channel in Myofibroblast Differentiation and Pulmonary Fibrosis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $528,264

## Abstract

PROJECT SUMMARY
Despite major advances in the understanding of the pathogenesis of pulmonary fibrosis, many of the therapies
that target the most well-studied genes and pathways have not achieved universal success in reversing or
even halting disease progression. This, along with the clinical heterogeneity of patients with idiopathic
pulmonary fibrosis (IPF), suggest that consideration of other genes in models of disease pathogenesis may be
useful. Fibroblasts from patients with IPF differ in the expression of many genes compared to normal
fibroblasts, and this laboratory has had a longstanding interest in identifying epigenetic changes that account
for these differences. KCNMB1 codes for the beta subunit of the large conductance (BK, Maxi-K, KCa1.1)
potassium channel and was identified in our previous microarray study as the top differentially methylated gene
in IPF fibroblasts. BK channels modulate potassium current and are well known to be important in vascular
tone and smooth muscle biology, but its importance in fibrosis has never been examined. We recently showed
in a publication that 1) KCNMB1 expression is increased in fibroblasts from IPF patients, 2) KCNMB1
contributes to increased BK channel activity, and 3) increased function of BK channels promote myofibroblast
differentiation, a hallmark of IPF. How it does so and whether this is sufficient to promote or worsen pulmonary
fibrosis in vivo is unknown. The objectives of this grant are to determine the mechanism of how BK channels
contribute to myofibroblast differentiation and establish the importance of BK channels to animal models of
pulmonary fibrosis. Our central hypothesis is that the epigenetic upregulation of KCNMB1 and increased BK
channel activity in IPF fibroblasts contribute to pulmonary fibrosis by promoting calcium signaling in fibroblasts,
which lead to myofibroblast differentiation. The First Aim is to establish the importance of BK channels to the
development of pulmonary fibrosis in vivo, and localize its pathogenic actions to lung fibroblasts. The Second
Aim is to delineate the mechanism by which BK channels contribute to myofibroblast differentiation, with the
hypothesis that BK channels promote intracellular calcium signaling, which is necessary for differentiation into
myofibroblasts. The Third Aim is to determine how expression of KCNMB1 is regulated in lung fibroblasts and
how profibrotic stimuli modulates opening and closing of BK channels. This proposal is significant because it
establishes BK channels as a novel, but important driver in the pathogenesis of pulmonary fibrosis.
Accomplishing these aims will also identify a mechanism and role for BK channels in the differentiation of
myofibroblasts that has never been previously described. Ultimately, these studies will serve to identify new
targets for future IPF therapeutics.

## Key facts

- **NIH application ID:** 10048967
- **Project number:** 2R01HL127203-06A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** STEVEN K HUANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $528,264
- **Award type:** 2
- **Project period:** 2015-04-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048967

## Citation

> US National Institutes of Health, RePORTER application 10048967, The Role of KCNMB1 and the Large Conductance Potassium (BK) Channel in Myofibroblast Differentiation and Pulmonary Fibrosis (2R01HL127203-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10048967. Licensed CC0.

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