# Therapeutic targeting of protein interactions to reverse MLCK1-mediated intestinal barrier loss and ameliorate disease.

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $780,557

## Abstract

SUMMARY
Increased intestinal permeability, i.e., barrier loss, is a common characteristic of many gastrointestinal and
systemic disorders and has been hypothesized to be a key contributor to disease progression. Animal models
of disease provide strong support for this hypothesis, but, due to the absence of drugs that reverse disease-
associated permeability increases, the therapeutic potential of intestinal barrier restoration is untested. Myosin
light chain kinase (MLCK) is a signaling node that, when activated, increases permeability. In inflammatory
bowel disease (IBD) patient biopsies, MLCK activity is upregulated and correlates with disease severity.
Recent studies have shown that inflammatory stimuli trigger recruitment of a specific MLCK isoform, MLCK1,
to the perijunctional cytoskeleton and that this MLCK1 recruitment is required for barrier loss. Further,
disruption of the MLCK1 interactome that directs recruitment is therapeutically superior to anti-TNF in
experimental IBD. Therefore, the long-term goal of this program is to create the detailed understanding that
will enable development of agents that target the MLCK1 interactome to restore barrier function and benefit
IBD patients. The overall objectives of this application are to i) discover the molecular basis of MLCK1
interactome function and ii) apply this knowledge to block MLCK1 recruitment in experimental IBD. The central
hypothesis is that prevention of MLCK1 interactome-dependent recruitment can restore the intestinal barrier.
The rationale for this project is that elucidating the molecular mechanisms of MLCK1 interactome function and
assessing the preclinical efficacy of targeting interactome components will create the scientific foundation
needed for translation to the clinic. The central hypothesis will be tested via three specific aims: i) define
mechanisms that regulate interactions between MLCK1 interactome components and identify sites that can be
targeted to disrupt these interactions; ii) determine how, when, and where these interactions are modified by
inflammatory signals and the potential of obstructing key interactions as a means to block MLCK1 recruitment
and restore barrier function in intestinal stem cell models; and iii) characterize the impact of interfering with
dynamic regulation of the MLCK1 interactome in preclinical mouse models and assess interactome staus in
patient biopsies. This proposal is conceptually and technically innovative because it will define function and
regulation of the newly-recognized MLCK1 interactome using sophisticated in vitro and in vivo models as well
as patient biopsies. These studies are significant because they are expected to create the structural and
mechanistic insight required for development of molecular therapies that modify unique MLCK1 interactome
functions to prevent or reverse barrier loss in IBD. Ultimately, advances that build on this critical information will
create a foundation for development of safe, non-immuno...

## Key facts

- **NIH application ID:** 10979706
- **Project number:** 2R01DK068271-19A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** JERROLD R. TURNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $780,557
- **Award type:** 2
- **Project period:** 2005-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979706

## Citation

> US National Institutes of Health, RePORTER application 10979706, Therapeutic targeting of protein interactions to reverse MLCK1-mediated intestinal barrier loss and ameliorate disease. (2R01DK068271-19A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10979706. Licensed CC0.

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