# Role of I-BAR proteins in enterocyte differentiation

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2020 · $406,547

## Abstract

SUMMARY
Brush border microvilli play essential roles in the processing and uptake of nutrients, and defense against
pathogenic microbes and toxic compounds that accumulate in the gut lumen. The destruction or malformation
of microvilli contributes to numerous intestinal pathologies, including illness caused by attaching and effacing
(A/E) pathogens such as Enterohemorrhagic E. coli O157:H7 (EHEC) and microvillus inclusion disease.
Despite functioning at a critical physiological interface in the gut, we know little about how microvilli are
assembled during the maturation of enterocytes that occurs as these cells exit the crypt. In this proposal, we
will begin to elucidate the molecular machinery that drives the growth of microvilli during enterocyte
differentiation. We recently discovered the Inverse Bin-Amphiphysin-Rvs (I-BAR) domain containing protein
Insulin Receptor Tyrosine Kinase Substrate (IRTKS) as a novel regulator of microvillar growth. BAR family
proteins are known drive and/or stabilize membrane curvature; I-BAR domains specifically interact with
membranes exhibiting outward curvature, like that generated during microvillar protrusion. Using super-
resolution microscopy, we found that IRTKS exhibits striking localization to the distal tips of microvilli, where
the growing ends of actin filaments are found. Based on this and other preliminary findings, we propose that
during enterocyte differentiation, IRTKS is recruited to regions of active brush border assembly to drive the
elongation of nascent microvilli. To test this hypothesis we propose to: (1) elucidate the function of IRTKS
during enterocyte differentiation in vivo, (2) define the mechanism underpinning IRTKS-induced microvillar
growth, and (3) identify upstream factors that regulate IRTKS localization and activity. These studies will
employ a combination of live imaging, state-of-the-art super-resolution microscopy, and new forms of electron
microscopy (EM) to test our central hypothesis in cell culture, enteroid, and mouse models. Successful
completion of these studies will lead to new paradigms for understanding intestinal epithelial morphogenesis
and disease.

## Key facts

- **NIH application ID:** 9856436
- **Project number:** 5R01DK111949-04
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** MATTHEW J TYSKA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $406,547
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856436

## Citation

> US National Institutes of Health, RePORTER application 9856436, Role of I-BAR proteins in enterocyte differentiation (5R01DK111949-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856436. Licensed CC0.

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