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Metabolic Regulation of Colonic Senescence and Pathological Implications: Epithelial and Microbial Interactions

Award Number: R01DK138355
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: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Metabolic Regulation of Colonic Senescence and Pathological Implications: Epithelial and Microbial Interactions - PROJECT SUMMARY/ABSTRACT Cellular senescence is a state of irreversible cell cycle arrest associated with macromolecular damage and secretion of senescence-associated secretory phenotype (SASP), which includes cytokines, chemokines, and growth factors. The SASP provides immune surveillance that recruits immune cells to clear senescent cells; however, persistent senescence or enduring SASP production that exceeds immune clearance aggravates inflammatory injuries. Ageing is a major driver of tissue senescence. Age-related accumulation of cellular senescence is a major pathogenic factor responsible for the decline of tissue function and the increase in age- related pathologies, but little is known about the molecular mechanism that drives tissue senescence. On the other hand, age-unrelated senescence and its pathophysiological impact are understudied. For example, very little is known about metabolic control of colonic senescence, its molecular mechanism and pathophysiological consequences. Our goal is to tackle these questions and fill the knowledge gaps. Our preliminary studies demonstrated that colon epithelial acetyl-CoA deficiency triggers robust p53-dependent colonic senescence, and the accompanying SASP induces severe mucosal and systemic inflammation leading to premature death in mice. Further investigation revealed that epithelial senescence and SASP are closely associated with inflammatory bowel disease (IBD) in both mouse colitis models and human patients. We also discovered that gut microbe-derived acetate helps maintain host's epithelial acetyl-CoA pool to prevent colonic senescence. Our data suggest that the acetyl-CoA status of colonic epithelial cells is determined by host ATP-citrate lyase (Acly), acetyl-CoA synthetase 2 (Acss2) and microbe-derived acetate; as such, gut dysbiosis, in the presence of Acly and Acss2 down-regulation, leads to acetyl-CoA deficiency that triggers colonic senescence. Our findings shed new lights on the development of age-unrelated colonic senescence and its pathogenic connection to mucosal inflammation and colitis, and suggest that colonic senescence presents a novel therapeutic target for IBD. To extend this investigation, we propose three Aims. In Aim 1 we will assess the effect of acetyl-CoA deficiency in intestinal stem cells on colonic homeostasis. In Aim 2 we will elucidate the molecular mechanism whereby nuclear/cytosolic acetyl-CoA deficiency triggers colonic senescence. In Aim 3 we will explore colonic senescence as a pathogenic driver as well as a novel therapeutic target of IBD. There are vast knowledge gaps about age-unrelated colonic senescence and its pathological effects. There are huge unmet needs for IBD therapy. This project will provide new mechanistic insights into metabolic control of colonic senescence, and unveil the critical roles of acetyl-CoA and microbe-derived acetate in the regulation of colonic senescence. For translational value, this project will uncover the link of colonic senescence to IBD pathogenesis and prove senescence not only as a novel biomarker of IBD but also as potential therapeutic target for IBD management.


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: 2026 ( Subtotal = $582,185 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/9/2026	NON-COMPETING CONTINUATION	$582,185
														Subtotal = $582,185

Issue Date FY: 2025 ( Subtotal = $523,967 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/20/2025	NON-COMPETING CONTINUATION	$523,967
														Subtotal = $523,967

Issue Date FY: 2024 ( Subtotal = $575,051 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/21/2024	NEW	$575,051
														Subtotal = $575,051

Grand Total All Awards = $1,681,203

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Metabolic Regulation of Colonic Senescence and Pathological Implications: Epithelial and Microbial Interactions

Award Number: R01DK138355

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: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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