# Impacting the pathophysiology of malabsorption induced by Myosin Vb inactivating mutations

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $365,376

## Abstract

Abstract
Myosin Vb (MYO5B) is a motor protein that is critical for cell polarization and protein trafficking towards the
apical membrane in epithelial cells. Inactivating MYO5B mutations cause the congenital diarrheal disease,
microvillus inclusion disease (MVID), which leads to life-threatening diarrhea and malabsorption. In MYO5B
knockout mice, as well as in MVID patient intestines, apical proteins that mediate nutrient and water absorption
are mis-localized away from the brush border of intestinal epithelial cells. We recently found that a bioactive
phospholipid, lysophosphatidic acid (LPA), can promote microvillus maturation and normalize localization of
sodium-dependent glucose cotransporter 1 and sodium/proton exchanger (NHE)3, important apical sodium
transporters that promote water absorption, both in MYO5B knockout tissues and organoids. However, LPA
injection did not significantly improve body weight loss induced by conditional MYO5B knockout in mice. We
hypothesize that the low solubility and fast degradation of natural LPA limit delivery of a sufficient dosage to
ameliorate intestinal deficits in vivo, and that potent LPA receptor (LPAR) agonists are more efficient. We
synthesized selective agonists for LPAR1 and LPAR5. Our preliminary data indicate that the LPAR5 agonist,
Compound-1, significantly improved villus/crypt ratios and apical NHE3 localization in MYO5B knockout mice.
We anticipate that LPAR5 activation can stimulate enterocyte differentiation and apical membrane trafficking
that bypass the blockades induced by loss of MYO5B function, leading to improved microvillus and villus
structure, nutrient transporter localization, and nutrient absorption. First, we will evaluate the therapeutic
potential of LPAR5 agonist treatment on epithelial cell function in mice with inactivating MYO5B mutations. In
addition to MYO5B deletion models, we will evaluate the effects of Compound-1 on mice with a G519R point
mutation in MYO5B (identified in a severe MVID patient). In addition to the mis-trafficking of nutrient
transporters, we have found that functional MYO5B loss induces cell lineage differentiation deficits. MYO5B
knockout mice show increased numbers of Paneth cells along with hyperproliferation, while sensory tuft cells
are reduced by 80%. LPA treatment reversed the tuft cell reductions in MYO5B knockout mice, suggesting that
LPA signaling enhances proper cell differentiation. Second, to specify MYO5B function in progenitor cells,
Myo5bflox/flox mice will be crossed with Lrig1-CreERT2 mice and the effects on epithelial proliferation and
differentiation will be characterized with or without Compound-1 treatment. Third, to understand the
mechanisms that underlie the hyperproliferation and differentiation deficits, we will determine the alterations in
cellular metabolic pathways in MYO5B-deficient mouse intestine before and after LPAR5 activation. We will
utilize imaging mass spectrometry techniques to provide spatial and quantitative ...

## Key facts

- **NIH application ID:** 10896167
- **Project number:** 5R01DK128190-04
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Izumi Kaji
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $365,376
- **Award type:** 5
- **Project period:** 2021-09-25 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896167

## Citation

> US National Institutes of Health, RePORTER application 10896167, Impacting the pathophysiology of malabsorption induced by Myosin Vb inactivating mutations (5R01DK128190-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10896167. Licensed CC0.

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