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The Impact of Circadian Misalignment on Colonic Barrier Homeostasis in Ulcerative Colitis

Award Number: R01DK124280
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Recently there has been compelling evidence that inflammatory bowel disease (IBD) subjects, both Crohn's disease (CD) and Ulcerative Colitis (UC), commonly have disrupted sleep, and disrupted sleep correlates with the risk of disease flare. Sleep/wake cycle, immune function, metabolism and multiple biological processes are all orchestrated by circadian rhythms. Circadian misalignment between the central circadian clock in the brain and environment has been found to contribute to a variety of metabolic and gastrointestinal tract (GIT) diseases. Yet, the prevalence and impact of circadian misalignment on IBD disease activity and GIT mucosal inflammation have not been established. The long-term objective of our research is to investigate the hypothesis that circadian malalignment worsens GIT mucosal inflammation and disease course in IBD. To test this hypothesis, we will conduct a prospective in lab study with human subjects on the impact of circadian misalignment in left sided mild to moderate Ulcerative Colitis. We will perform two circadian measures phase assessments under strictly controlled laboratory conditions at: 1) baseline, and after 2) circadian misalignment after three days of simulated night shifts in both inactive UC patients and healthy control subjects. To test the hypothesis that UC patients (compared to healthy subject controls) are less resilient to circadian misalignment we will assess: time impact of our protocol on circadian rhythms (Aim 1) by the following: phase angle of entrainment [time from dim light melatonin onset to sleep onset] (Aim1a); peripheral circadian rhythms by clock gene expression in colonic tissue from a flexible sigmoidoscopy and in subjects peripheral blood mononuclear cells (Aim1b); and colonic clock gene expression and Per2::Luc activity over 24 hours utilizing an in-vitro model of colonic organoids (Aim1c). Next, we will test the hypothesis that circadian misalignment will increase colonic permeability and mucosal inflammation in UC patients (vs. Controls) (Aim2) through the following: endoscopy score, stool calprotectin, colonic barrier (permeability, AJC proteins), and markers of systemic barrier function and inflammation (Aim 2a); adversely impacting microbial community structure/function (Aim 2b); and use 2D colonic organoid monolayers to explore ex-vivo barrier function by co- culturing with TNF-α/INF-γ (Aim 2c). The results of this innovative proposal will greatly increase our understanding of the important role circadian misalignment may have in UC disease activity and colonic inflammation, and identify new circadian regulated targets for treatment in UC.


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 = $598,178 )
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	4	5/30/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$36,588
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	3/1/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$24,519
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	2/28/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$537,071
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	006	4	6/24/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$950,222
2024	2023	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	3	6/24/2024	NON-COMPETING CONTINUATION	-$601,038
2024	2023	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/28/2024	NON-COMPETING CONTINUATION	$0
2024	2022	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	2	6/24/2024	NON-COMPETING CONTINUATION	-$349,184
														Subtotal = $598,178

Issue Date FY: 2023 ( Subtotal = $601,038 )
2023	2023	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PKWY	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/17/2023	NON-COMPETING CONTINUATION	$601,038
														Subtotal = $601,038

Issue Date FY: 2022 ( Subtotal = $588,018 )
2022	2022	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/25/2022	NON-COMPETING CONTINUATION	$529,216
2022	2022	RUSH UNIVERSITY MEDICAL CENTER	1620 W HARRISON ST	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/30/2022	NON-COMPETING CONTINUATION	$58,802
														Subtotal = $588,018

Issue Date FY: 2021 ( Subtotal = $601,275 )
2021	2021	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/19/2021	NEW	$601,275
														Subtotal = $601,275

Grand Total All Awards = $2,388,509

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The Impact of Circadian Misalignment on Colonic Barrier Homeostasis in Ulcerative Colitis

Award Number: R01DK124280

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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