# Deciphering mechanobiology in human diseases by developing a TMEM63B channelopathy mouse model

> **NIH NIH R21** · DUKE UNIVERSITY · 2024 · $193,101

## Abstract

SUMMARY
Cells rely on precise sensing and prompt responses to mechanical and osmotic changes to maintain
functionality and survival. Recent breakthroughs, including the identification of mechanosensitive and
osmo-sensitive ion channels, have revolutionized our understanding of cellular responses to these
stimuli. Despite this, the pathophysiological mechanisms of these processes in disease remain
elusive. In this application, we aim to address this knowledge gap by creating a mouse model with a
human gain-of-function V44M mutation of TMEM63B, a newly discovered mechano- and osmo-sensing
ion channel. The V44M TMEM63B channelopathy is associated with a diverse range of human
symptoms, including epilepsy, intellectual disabilities, and distinctive blood cell disorders. Our
preliminary studies revealed an unexpected trait of the V44M mutation. This channelopathy mutation not
only alter the ion channel activity of TMEM63B but also bestows a novel function that has been lost in
TMEM63 proteins during evolution. Specifically, the V44M mutation enables lipid scrambling - the
bidirectional translocation of lipids across cell membranes. This function is reminiscent of the capabilities
seen in TMEM63B's evolutionary cousins, the TMEM16 lipid scramblases. To explore the in vivo
implications of this mutation in human diseases, we propose creating a TMEM63B-V44M knockin
mouse with controlled cell-type specific expression. This model will allow specifically dissect the
mutated ion channel's role and its newfound lipid transport property across various cell types and
disease contexts. Post-validation with our robust functional assays in this application, this mouse line
will be made available to researchers across diverse disciplines including hematology, neurobiology,
and more. This pioneering TMEM63B channelopathy mouse model will be invaluable to uncover the
unknown pathophysiology of this mysterious mechano- and osmo-sensing ion channels in health and
disease and shine light on therapeutics to treat TMEM63B related diseases.

## Key facts

- **NIH application ID:** 11031805
- **Project number:** 1R21OD037849-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Huanghe Yang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $193,101
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11031805

## Citation

> US National Institutes of Health, RePORTER application 11031805, Deciphering mechanobiology in human diseases by developing a TMEM63B channelopathy mouse model (1R21OD037849-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11031805. Licensed CC0.

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