# The role of Myosin Vb in hepatocyte protein trafficking

> **NIH NIH K01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $133,463

## Abstract

PROJECT SUMMARY
Background and aims: Microvillus Inclusion Disease (MVID) is a form of congenital diarrhea caused by
inactivating mutations in Myosin Vb (MYO5B). The available treatment options for individuals with MVID are
either lifelong total parenteral nutrition or full intestinal transplantation. MVID patients frequently present with
cholestasis. This cholestasis was previously thought to arise from prolonged administration of total parenteral
nutrition. However, recent publications have described mutations in MYO5B that do not result in MVID, but
instead patients have isolated cholestasis. Given the complex nature of MVID and the limited treatment options
available, understanding the pathogenesis of cholestasis resulting from mutations in MYO5B represents an
important scientific question which needs to be addressed. The central hypothesis of this research proposal is
that mutations in MYO5B result in aberrant expression of apical/canalicular membrane transporters preventing
the normal secretion of bile salts. We base our hypothesis on preliminary data generated from our mouse and
pig models of MVID which demonstrate mislocalization of BSEP and other canalicular transporters. Our
findings are mirrored by published reports from patients with mutations in MYO5B, demonstrating aberrant
expression of the bile salt export protein (BSEP) in hepatocytes. To date, no experimental animal model has
been used to define the mechanism of cholestasis in the setting of MVID. For this K01 Career Development
Award, I propose the use of germline MYO5B KO mice, an MVID pig model and a novel mouse model of
MYO5B point mutation to address deficits in apical transporters in hepatocytes that arise from mutations in
MYO5B. Specific Aim 1 will define the function of MYO5B in maintaining hepatocyte polarity and
homeostasis. Specific Aim 2 will determine the mechanism by which the C266R mutation in MYO5B
contributes to cholestasis, but does not result in MVID. At the completion of these studies I expect to have
elucidated the role of MYO5B in the regulation of protein trafficking in hepatocytes in vivo and in vitro. This
proposal highlights the need for a better understanding of the function of MYO5B in hepatocytes with the
ultimate goal of improving current therapeutic treatments for MVID. Long-term objective and aims: Being the
recipient of a K01 Career Development Award would provide the mentorship, training and support necessary to
achieve my goal of becoming an independent investigator. This research is well suited for the National Institute
of Diabetes and Digestive and Kidney Diseases as it relates to digestive and liver disorders. Vanderbilt
University Medical Center offers all of the scientific resources required to complete this proposal. I have
assembled a group of renowned scientists to serve as my mentors and mentorship committee, and as
collaborators. Additionally, I have developed a training plan to enhance my scientific repertoire, increase my
publicat...

## Key facts

- **NIH application ID:** 9990777
- **Project number:** 5K01DK121869-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Amy C Engevik
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $133,463
- **Award type:** 5
- **Project period:** 2019-08-07 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990777

## Citation

> US National Institutes of Health, RePORTER application 9990777, The role of Myosin Vb in hepatocyte protein trafficking (5K01DK121869-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9990777. Licensed CC0.

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