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IL-27 receptor signaling in the maintenance of intestinal barrier after ethanol and burn injury

Award Number: F30DK123929
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Project Summary/Abstract The goal of this project is to better understand how interleukin-27 (IL-27) signaling in intestinal epithelial cells (IEC) can promote intestinal barrier integrity in the setting of ethanol intoxication and burn injury. Burn injuries account for 40,000 hospitalizations every year, with nearly 50% of patients having detectable blood alcohol levels at the time of admission. Patients intoxicated at the time of burn injury have worse clinical outcomes, including longer hospital stays, increased rates of infection, and increased morbidity and mortality. Detrimental sequelae of burn injuries are the result of the breakdown in the gut barrier, which normally encloses the largest reservoir of bacteria and harmful bacterial products. Ethanol intoxication at the time of burn injury exacerbates this post-burn pathogenesis, leading to exacerbated gut barrier dysfunction and leakiness. This gut barrier breakdown leads to multiple organ failure, sepsis, and death following injury. A major contributing factor to gut leakiness is attributed to hypoxic conditions in the gut, leading to stabilization of hypoxia inducible factor 1a (HIF1a). Our lab has previously found that inhibition of HIF1a with PX-478 leads to improved outcomes in ethanol intoxication and burn injury, including improved gut transit, decreased gut permeability, and reduced inflammation. However, the mechanism by which this occurs is unknown. We have also found that expression of the IL-27 receptor was restored in IECs following inhibition of HIF1a following ethanol intoxication and burn injury. Ethanol intoxication and burn injury led to reduced IL-27 producing cells in the lamina propria, which is accompanied by reduced IL-27 receptor expression in IECs. IL-27 has been implicated in restoring intestinal barrier integrity in other models of intestinal inflammation, therefore leading us to hypothesize that restoring IL- 27 signaling following ethanol intoxication and burn injury will lead to improved barrier integrity. In Aim 1, we will determine perturbations in IL-27 signaling in the intestine following HIF1a inhibition in ethanol intoxication and burn injury. In Aim 2, we will elucidate the mechanism by which IL-27 signaling restores intestinal epithelial barrier integrity by observing changes in phosphorylation of downstream signaling molecules STAT1/STAT3, IEC proliferation, and tight junction expression. Overall, this study will aid in our understanding of how we can restore intestinal barrier function following ethanol intoxication and burn injury.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$27,055 )
2024	2022	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/28/2023	NON-COMPETING CONTINUATION	-$27,055
														Subtotal = -$27,055

Issue Date FY: 2022 ( Subtotal = $51,752 )
2022	2022	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	12/13/2021	NON-COMPETING CONTINUATION	$36,018
2022	2022	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/10/2022	NON-COMPETING CONTINUATION	$358
2022	2022	LOYOLA UNIVERSITY OF CHICAGO	2160 S 1ST AVE	MAYWOOD	IL	60153	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	7/20/2022	NON-COMPETING CONTINUATION	$15,376
														Subtotal = $51,752

Issue Date FY: 2021 ( Subtotal = $32,848 )
2021	2021	LOYOLA UNIVERSITY OF CHICAGO	2160 S FIRST AVE	MAYWOOD	IL	60153	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/8/2021	NON-COMPETING CONTINUATION	$516
2021	2021	LOYOLA UNIVERSITY OF CHICAGO	2160 S FIRST AVE	MAYWOOD	IL	60153	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/17/2020	NON-COMPETING CONTINUATION	$32,332
														Subtotal = $32,848

Issue Date FY: 2020 ( Subtotal = $32,332 )
2020	2020	LOYOLA UNIVERSITY OF CHICAGO	2160 S FIRST AVE	MAYWOOD	IL	60153	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	2/13/2020	NEW	$0
2020	2020	LOYOLA UNIVERSITY OF CHICAGO	2160 S FIRST AVE	MAYWOOD	IL	60153	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	2/13/2020	NEW	$504
2020	2020	LOYOLA UNIVERSITY OF CHICAGO	2160 S FIRST AVE	MAYWOOD	IL	60153	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/31/2020	NEW	$31,828
														Subtotal = $32,332

Grand Total All Awards = $89,877

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IL-27 receptor signaling in the maintenance of intestinal barrier after ethanol and burn injury

Award Number: F30DK123929

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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