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Intestinal IL-17RA signaling and mucosal host defense

Award Number: R01DK121798
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Intestinal IL-17RA signaling and mucosal host defense - Inflammatory bowel disease (IBD), which comprises Ulcerative Colitis (UC) and Crohn’s Disease (CD), is a devastating disease that impacts millions of people in the United States. The underlying mechanisms leading to IBD are poorly understood. Paneth cells and their antimicrobial products (a-defensins, lysozyme etc.) play a critical role in small intestinal host defense and their dysregulation constitutes a pathogenic factor for CD. CD patients have Paneth cell abnormalities, reduced expression of a-defensins and elevated levels of IL-17A in the inflamed tissue. The IL-17A/IL-17F axis is a known driver of intestinal inflammatory and protective responses in mouse models and human IBD, but little is known regarding the specific cellular niches of IL- 17A/F receptor signaling and the molecular mechanisms of IL-17A-mediated host defense in the intestines. We were the first to show that the abrogation of intestinal IL-17A host defense responses leads to commensal dysbiosis and dysregulated immune responses in the small intestine. Despite the myriad of gastrointestinal tract responses to IL-17A stimulation, the literature has failed to elucidate whether the defense responses to injury or infection are a result of direct stimulation to functionally distinct absorptive or secretory mature epithelial cell types or if they are stem cell-derived consequences. Therefore, it is not known whether IL-17A directly or indirectly modulates Paneth and other cell types effector function in the gut. We found that IL-17A/F receptor (IL-17RA/IL-17RC) is expressed on functionally distinct absorptive cells (enterocytes), secretory cells (Paneth), Lgr5+ intestinal stem cells (ISCs) and transit-amplifying (TA) progenitor cells of the intestine. However, almost nothing is known regarding whether IL-17A directly or indirectly modulates Paneth cells, ISCs and progenitor cells function. We now have compelling evidence suggesting that IL-17A directly regulates unique and specific functions in Paneth cells, ISCs and ATOH1+ progenitor cells of intestine. ATOH1 is required for lineage commitment of intestinal secretory cells, including Paneth cells. To investigate lineage- specific function, we generated and validated entire gut epithelium (Villin-cre), Paneth cell (Defa6-cre) and Atoh1-specific (Atoh1-cre) novel IL-17RA (Il17rafl/fl) conditional knockout mice. The proposed studies in Aim 1 will seek to understand the role of IL-17RA signaling in regulating ISC and Paneth cell function under homeostatic conditions. In Aim 2, using multiple models of intestinal inflammation and our lineage-specific IL- 17RA conditional knockout mice, we will determine how IL-17A regulates unique and novel functions in specific cell types in the small and large intestine, respectively. These studies will have a direct impact in IBD research to understand the novel role of IL-17RA signaling major cell types of the small and large intestine. Completion of these studies will provide a needed understanding of the complex molecular mechanisms of actions of IL- 17A in regulating intestinal inflammation.


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 = -$3,905 )
2025	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	9/29/2025	NON-COMPETING CONTINUATION	-$3,905
														Subtotal = -$3,905

Issue Date FY: 2023 ( Subtotal = $412,984 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/20/2023	NON-COMPETING CONTINUATION	$412,984
														Subtotal = $412,984

Issue Date FY: 2022 ( Subtotal = $412,984 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/7/2022	NON-COMPETING CONTINUATION	$412,984
														Subtotal = $412,984

Issue Date FY: 2021 ( Subtotal = $412,984 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	4/21/2021	NON-COMPETING CONTINUATION	$412,984
														Subtotal = $412,984

Issue Date FY: 2020 ( Subtotal = $412,984 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/3/2020	NON-COMPETING CONTINUATION	$412,984
														Subtotal = $412,984

Issue Date FY: 2019 ( Subtotal = $412,984 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/24/2019	NEW	$412,984
														Subtotal = $412,984

Grand Total All Awards = $2,061,015

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Intestinal IL-17RA signaling and mucosal host defense

Award Number: R01DK121798

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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