# Mechanisms of Intestinal Integrity in Sepsis and Shock

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $327,600

## Abstract

Sepsis is the leading cause of death among critically ill patients in the United States with between 230,000 and
370,000 people dying from the disease annually. Outside of antibiotics, treatment for sepsis is non-specific,
and there are no approved therapeutics available once antibiotics and supportive therapy fail. The gut has long
been characterized as the motor of multiple organ dysfunction syndrome. We have spent the three previous
cycles of funding examining mechanisms of gut integrity (first apoptosis then proliferation, migration and
permeability) in sepsis. This renewal is a logical next step in the evolution of how we view the gut in sepsis. We
propose to assay the intestinal epithelium, immune system and microbiome, both in isolation and also in the
context of how alterations in one compartment impact the others since we hypothesize this strategy will yield
insights that can only be obtained using this more comprehensive approach. The first goal of the proposal is to
understand mechanisms through which the immune system and microbiome alter survival in mice lacking the
tight junction-associated protein junctional adhesion molecule-A (JAM-A), which have alterations in
permeability, bacteremia and survival following sepsis. This will be done using a combination of mice with
whole body and intestine-specific deletion of JAM-A as well as mice with controlled alterations in the
endogenous bacteria. Further, intestinal permeability is controlled by two tight junction-dependent pathways
and a tight junction-independent pathway. Each allows different size molecules to exit the gut lumen into the
extraluminal environment. By genetically altering each of these pathways of permeability (the leak, pore and
unrestricted pathways respectively), studies will determine the functional significance of each together and in
isolation in sepsis. Finally, migration is slowed along the intestine during sepsis, with cells residing nearly twice
as long during sepsis as under basal conditions, mediated, at least in part, by apoptosis and proliferation.
Mechanisms of slowed migration will be determined including the impact of altering permeability and the
microbiome. Since the gut plays a major role in both initiating and propagating critical illness, understanding
mechanisms through which gut integrity is dysregulated in sepsis has significant public health implications in a
disease that is common, very costly, and highly lethal.

## Key facts

- **NIH application ID:** 10240524
- **Project number:** 5R01GM072808-17
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Craig M Coopersmith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $327,600
- **Award type:** 5
- **Project period:** 2005-09-06 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240524

## Citation

> US National Institutes of Health, RePORTER application 10240524, Mechanisms of Intestinal Integrity in Sepsis and Shock (5R01GM072808-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10240524. Licensed CC0.

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