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REGULATION OF NICHE CELL DIFFERENTIATION TO SUSTAIN INTESTINAL STEM CELL REGENERATION AGAINST GUT INFLAMMATION

Award Number: R01DK123299
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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REGULATION OF NICHE CELL DIFFERENTIATION TO SUSTAIN INTESTINAL STEM CELL REGENERATION AGAINST GUT INFLAMMATION - Project Summary: Intestinal Clostridium difficile infection (CDI) has increased in patients with inflammatory bowel disease (IBD) over the past decade, resulting in a major healthcare burden. Therapeutic approaches for this comorbidity are extremely limited, however, due to the current lack of understanding of the essential cell types and key signaling proteins involved in CDI that exacerbate IBD. It is believed that along with niche cells, Lgr5hi and Lgr5low intestinal epithelial stem cells (IESCs) control intestinal epithelial (IEC) lineage repair following acute mucosal injuries. Further, the formation of intestinal Paneth cell (PC) or colonic deep crypt secretory cell (DCS) niche cells are differentially regulated by opposing Wnt and Notch signaling. Inducing IESCs to give rise to these niche cells could mitigate CDI in the setting of IBD or promote IESC repair of IECs in IBD. However, how IESCs are sustained to specify PCs and DSCs that in turn sustain IESC regeneration remains unclear. We reported that the activation of Tyrosine phosphorylated (pYSTAT5) promoted IESC regeneration following acute ileitis and colitis. Importantly, single nucleotide polymorphisms (SNPs) in JAK2 or STAT5A have been linked to IEC healing defects, CDI, and IBD complications. JAK2 SNP carriage is associated with two-fold higher rates of CDI in pediatric Crohn’s disease with synchronous ileal-colonic location (ileocolitis). However, whether JAK2 or STAT5A SNPs in IBD are critical to determine the susceptibility to comorbid CDI is not known. Our current data show that a single STAT5A SNP reduces stem cell survival. Stat5 depletion leads to a severe pseudomembranous colitis compared to controls; in contrast, constitutively active STAT5A (Ca-pYSTAT5) reactivates Lgr5low IESCs toward PCs and increases production of secreted niche factors. Therefore, we hypothesize that Ca-pYSTAT5 regulates IESCs to give rise to PC and DCS niche cells that in turn sustain IESC regeneration and that the SNPs in the JAK2-STAT5 pathway impair Ca-pYSTAT5, leading to IBD with comorbid CDI. We will test this hypothesis by addressing the following Specific Aims. In Aim 1, we will examine the effects of genetic defects in JAK2-STAT5 on IBD and CDI comorbidity rates, IESC regeneration, and niche cell differentiation. We will test the effects of JAK2 or STAT5A SNP on de novo IESC niche cell differentiation. These studies will determine why CDI frequently occurs in IBD and will suggest a potential therapeutic target to reduce the prevalence of CDI with IBD. In Aim 2, we will define the mechanisms by which Ca-pYSTAT5 regulates IESC niche cell differentiation. We will determine the effects of reduced Stat5 expression, pYSTAT5 level and knock-in of the STAT5A SNP in mice on the susceptibility of colitis to CDI. These studies will test the link between defective JAK2-pYSTAT5 and IBD comorbid with CDI. Collectively, our proposal will identify an intestinal lineage-restricted transcription factor for IESCs to induce niche cells, which in turn protect IESC regeneration against IBD with comorbid CDI. Our studies will provide critical insights into mechanisms of JAK2 and STAT5A risk polymorphisms in the context of IBD and CDI.


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: 2025 ( Subtotal = $0 )
2025	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $349,898 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/24/2023	NON-COMPETING CONTINUATION	$349,898
														Subtotal = $349,898

Issue Date FY: 2022 ( Subtotal = $354,859 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/29/2022	NON-COMPETING CONTINUATION	$35,486
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/11/2022	NON-COMPETING CONTINUATION	$319,373
														Subtotal = $354,859

Issue Date FY: 2021 ( Subtotal = $359,778 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/11/2021	NON-COMPETING CONTINUATION	$357,750
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	8/16/2021	NON-COMPETING CONTINUATION	-$163,409
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	8/17/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$165,437
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	3	8/31/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$361,235
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	2	8/31/2021	NON-COMPETING CONTINUATION	-$194,341
2021	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	1	8/31/2021	NEW	-$166,894
														Subtotal = $359,778

Issue Date FY: 2020 ( Subtotal = $357,750 )
2020	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/30/2019	NEW	$357,750
														Subtotal = $357,750

Grand Total All Awards = $1,422,285

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REGULATION OF NICHE CELL DIFFERENTIATION TO SUSTAIN INTESTINAL STEM CELL REGENERATION AGAINST GUT INFLAMMATION

Award Number: R01DK123299

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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