# PHARMACOLOGICAL MODULATION OF PIEZO1 CHANNELS

> **NIH NIH R01** · WESTERN UNIVERSITY OF HEALTH SCIENCES · 2024 · $367,685

## Abstract

Summary
Mechanosensitive Piezo ion channels enable eukaryotic cells to sense mechanical forces. In
vertebrates, two Piezo homologs, Piezo1 and Piezo2, play central roles in all major physiological
systems and are associated with numerous diseases including hypertension, xerocytosis,
lymphedema, arthrogryposis, inflammation, pain, and cancer progression. Hence, pharmacological
modulation of specific Piezo homologs could help treat many human ailments. Yet, this effort is
currently limited by the paucity of homolog-selective pharmacological agents and the lack of a
clear molecular understanding by which Piezo channels open and close their pore in response to
physical and chemical stimuli. To bridge this gap, this proposal will leverage a recently identified
pharmacological binding site in mammalian Piezo1 channels. Specifically, we will use reverse
genetics, high-resolution electrophysiology, and calcium imaging to dissect structural pathways
by which the binding of the small molecule Yoda1 energetically promotes an open state (Aim 1).
In parallel, we will deploy an innovative, multi-pronged approach combining binding free energy
calculations, structure-activity relationships, machine learning-based virtual screening of ultra-
large billion-compounds library, and rapid experimental screening assays to identify novel
molecules that preferentially bind conducting or non-conducting channel conformations, thus
potentially acting as Piezo1 activators and inhibitors, respectively (Aim 2). Successful completion
of this project will identify discrete mechanotrasnduction pathways associated with
pharmacological activation of Piezo1 channels and identify novel pharmacological activators and
inhibitors of Piezo1 channels with potential research and clinical value.

## Key facts

- **NIH application ID:** 10909846
- **Project number:** 5R01GM130834-06
- **Recipient organization:** WESTERN UNIVERSITY OF HEALTH SCIENCES
- **Principal Investigator:** Yun Lyna LUO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $367,685
- **Award type:** 5
- **Project period:** 2019-09-05 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909846

## Citation

> US National Institutes of Health, RePORTER application 10909846, PHARMACOLOGICAL MODULATION OF PIEZO1 CHANNELS (5R01GM130834-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10909846. Licensed CC0.

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