# Biophysical Modulation of Cardiac Ion Channels by MicroRNA

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2024 · $638,349

## Abstract

Project Summary
MicroRNAs (miRs) are evolutionally conserved small non-coding RNA molecules that are broadly involved in
regulating most biological events; previous studies have focused on the canonical mRNA interference (RNAi)
mechanism of miRs. During the previous funding period, we were the first to unveil an evolutionarily-
conserved novel biophysical action for miRs beyond its RNAi mechanism. Specifically, we revealed a
novel biophysical action of miR1, which is the most predominant miR in the heart and is downregulated in
human heart failure. We found that miR1 physically binds to an inward rectifier potassium channel Kir2.1,
directly suppresses the IK1 current and biophysically modulates cardiac cellular electrophysiology. Importantly,
we found that a human single nucleotide polymorphism (hSNP) of miR1–– hSNP14A/G (rs776480338), in
which the 14th nucleotide “A” is mutated to “G”, is a RNAi-only variant that specifically abolishes the biophysical
action while maintaining the RNAi function of miR1, validating that the biophysical modulation is independent
of RNAi. Our discoveries suggest that miRs modulate cardiac homeostasis through two different mechanisms:
1) canonical RNAi that regulates the expression of proteins, including ion channels, and 2) newly-discovered
mechanism of direct binding with proteins that quickly results in functional modulation. With this important
new finding, it is now imperative to investigate if multiple cardiac ion channels are biophysically modulated by
miRs and to elucidate the specific physiological impact of miR1’s biophysical action in the regulation of cardiac
(electro)physiology. Based on our published findings and preliminary data, we hypothesize that the
biophysical modulation of cardiac ion channels by miRs is a general regulatory mechanism that exists broadly
and plays a critical role in the homeostasis of the heart. We will study this with the following specific aims. 1)
To investigate the biophysical modulation of cardiac ion channels by miR1, 2) To understand the physiological
impact of miRs’ biophysical action on the heart, 3) To unveil the general mechanisms guiding miRs’
biophysical modulation of cardiac ion channels. In addition to a broad range of cellular activities regulated by
the large number of miRs (>30,000 miRs in >200 species) and ion channels, our study will significantly and
innovatively expand the biological significance of miR biology and ion channel biology with broad implications.
Our discoveries have pioneered a new field in miR biology and will provide a mechanistic foundation and new
avenue of RNA-medicine development for antiarrhythmic therapy.

## Key facts

- **NIH application ID:** 10832698
- **Project number:** 5R01HL139006-06
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Isabelle Deschenes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $638,349
- **Award type:** 5
- **Project period:** 2017-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832698

## Citation

> US National Institutes of Health, RePORTER application 10832698, Biophysical Modulation of Cardiac Ion Channels by MicroRNA (5R01HL139006-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10832698. Licensed CC0.

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