# Small GTP Binding Proteins in Gastrointestinal Mucosa

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $384,899

## Abstract

Trafficking of apical transporters and enzymes to the enterocyte brush border is critical for the establishment of
normal fluid, nutrient and electrolyte absorption from the gut lumen. Similarly, establishment of the normal
compendium of proteins at the intercellular tight and adherens junctions determines the integrity of epithelial
barrier function. Aberrations in either apical trafficking or junctional integrity lead to enteric pathologies
including diarrhea, constipation and intestinal barrier dysfunction. Investigations over the past decade have
established that components of the Rab11a and Rab8a-dependent membrane recycling systems regulate
trafficking of apical membrane and junctional proteins required for the maintenance of proper apical polarity.
Loss of functional Myosin Vb (MYO5B) leads to severe diarrhea due to loss of apical transporters secondary to
deficits in Rab11a and Rab8a-dependent apical trafficking as observed in neonates with Microvillus Inclusion
Disease (MVID). At the same time, the Rab11a-interacting proteins, Rab11-FIP1 and Rab11-FIP2, regulate
junctional structure and function, in part through their phosphorylation by the critical polarity-related kinase
MARK2/Par1b. All of these studies have led to the recognition that the coordinated regulation of apical polarity
and trafficking by components of the apical recycling system lies at the heart of enterocyte physiology and
pathophysiology. We have hypothesized that pathways through aspects of the recycling system provide for
specificity of trafficking of particular cargoes to the apical membrane and the intercellular junctions. The apical
recycling system represents a critical target for intervention in pathophysiologies that undermine apical
membrane trafficking to the brush border and establishment of functional junctional integrity. To analyze this
hypothesis, we will pursue two specific aims: First, we will determine the roles of elements of the apical
recycling system in trafficking of ion transporters and enzymes to the enterocyte apical brush border. These
studies will examine the fates of endogenous enterocyte apical proteins in human intestinal enteroids
differentiated on two-dimensional monolayer cultures on permeable membranes. Second, we will examine the
role of Rab11-FIP1B and its phosphorylation by MARK2/Par1b in the regulation of intestinal enterocyte
junctional function. These studies will allow a greater understanding of how phosphorylation of Rab11-FIP1B
regulates trafficking to and maintenance of junctions.
Impact: These studies will identify components of the apical recycling system that may regulate apical
trafficking of particular brush border and junctional cargoes. Definition of the multiple pathways for apical
cargo trafficking to the brush border and junctions will provide insights into how disruption of specific pathways
may alter physiology and how pathophysiological loss of trafficking may be restored through rerouting of
proteins to alternat...

## Key facts

- **NIH application ID:** 9979847
- **Project number:** 5R01DK048370-25
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** James Richard Goldenring
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $384,899
- **Award type:** 5
- **Project period:** 1997-08-15 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979847

## Citation

> US National Institutes of Health, RePORTER application 9979847, Small GTP Binding Proteins in Gastrointestinal Mucosa (5R01DK048370-25). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9979847. Licensed CC0.

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