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PARP1 and PARylation as novel effectors of gut inflammation

Award Number: R01DK136240
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: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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PARP1 and PARylation as novel effectors of gut inflammation - Despite recent advances in the understanding host-microbiome interactions in the pathogenesis of Inflammatory Bowel Diseases (IBD), the complexity of the host’s response to changing gut microbiota is daunting and still incompletely understood. In this proposal, we show that poly-ADP-ribosylation (PARylation), a post-translational modification that involves the enzymatic transfer of ADP-ribose (ADPr) from NAD+ to specific amino acids of target proteins, plays key roles as a mediator of inflammatory response in the gut. For the first time, we provide evidence that PARP1 is the primary PAR writer in the colon, where it serves as a powerful transcriptional modulator. Commensal bacteria are necessary for mucosal PARP1 activity and PARylation and, reciprocally, PARP1 controls the microbial composition and metabolic activity, modulates colonic epithelial barrier function, and restricts the mucosal Treg compartment. Importantly, human and murine colitis is associated with mucosal hyperPARylation, which can be transferred to germ-free mice with complex microbial community from IBD patients. Total or epithelial-specific knockout of PARP1 (or pharmacological inhibition) protect from and promote recovery from mucosal injury. Based on these novel preliminary observations, we hypothesized that hyperPARylation is a significant contributor to mucosal inflammation and impaired mucosal restitution via both extrinsic (interaction with gut microbiota) and intrinsic effects in the colonic mucosa. We will address this hypothesis in the following three well-integrated, but not mutually contingent specific aims, which will: (1) Define the role of NAD+ depletion vs. hyperPARylation as putative culprits in the pathogenesis of experimental colitis (2) Define the role of PARP1 and PARylation in colitis mediated by human IBD microbiota; and (3) Mechanistically define the roles of PARP1 in the highly interactive relationship between gut microbiota and epithelial barrier function and mucosal restitution.in the inflamed colon. This novel research plan will greatly advance the field of fundamental mucosal biology and will offer targeting of PARP1 activity as a potential IBD therapy.


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 = $626,295 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/29/2025	NON-COMPETING CONTINUATION	$626,295
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/29/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $626,295

Issue Date FY: 2024 ( Subtotal = $640,056 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	8/27/2024	SUPPLEMENT FOR EXPANSION	$38,812
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/3/2024	NON-COMPETING CONTINUATION	$601,244
														Subtotal = $640,056

Issue Date FY: 2023 ( Subtotal = $615,535 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/25/2023	NEW	$615,535
														Subtotal = $615,535

Grand Total All Awards = $1,881,886

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PARP1 and PARylation as novel effectors of gut inflammation

Award Number: R01DK136240

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: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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