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Senescent hepatocytes mediate reprogramming of immune cells in acute liver failure

Award Number: F31DK134197
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/15/2023
PERIOD OF PERFORMANCE END DATE: 04/01/2024

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Senescent hepatocytes mediate reprogramming of immune cells in acute liver failure - PROJECT SUMMARY Acute liver failure (ALF) is characterized by coagulopathy, hepatic encephalopathy, jaundice and multi-organ failure. Fifty percent of all ALF cases in the United States and UK are due to acetaminophen (APAP) overdose. Supraphysiological doses of APAP overwhelm safe detoxification pathways in the liver leading to excessive bioactivation of APAP by Cyp2e1 into the highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). This initiates a cascade of intracellular events driving hepatocyte death. An extensive body of work has elucidated the molecular mechanisms of hepatocyte necrosis during APAP overdose, but detailed mechanisms involved in the development of ALF have been largely unexplored. The innate immune response after liver injury plays a critical role in liver recovery in the human relevant mouse model of APAP overdose. However, immune cell dysfunction has been implicated in the development of ALF. Though crosstalk between stressed hepatocytes and immune cells actively supports liver recovery, persistent and prolonged hepatocyte stress may alter this communication network, resulting in immune cell reprogramming towards detrimental phenotypes which facilitate ALF. Excessive cell stress can elicit temporary or permanent cell cycle arrest, a cell fate decision called senescence. Some cells acquire a senescent associated secretory phenotype (SASP) which can elicit pleotropic effects on nearby cells and the tissue microenvironment. Our preliminary data demonstrate that Klf6 and p21 induce hepatocyte senescence after a severe APAP overdose and that these hepatocytes have an active SASP, enriched in the cytokine Cxcl14 which persists in circulation. These key findings lead us to hypothesize that upon severe APAP-induced liver injury, prolonged hepatocyte senescence results in a sustained secretome exposure enriched in Cxcl14 causing immune cell reprogramming impeding tissue repair and injury resolution. This hypothesis will be tested by pursuit of two specific aims. Experiments in Aim 1 are designed to evaluate how Klf6 induces p21 and Cxcl14 and the influence of in vivo silencing of Klf6 on APAP-induced senescence and liver recovery after injury. Aim 2 will use single-cell RNA sequencing in combination with wet-lab approaches to define how the critical SASP component Cxcl14 alters the global communication network between senescent hepatocytes and immune cells after a severe APAP overdose. Collectively, these data will define the molecular mechanisms responsible for sustained induction of hepatocyte senescence, its relationship to the induction of a senescent associated secretory phenotype, and the signaling interactions between senescent hepatocytes and the innate immune response. This proposed work will provide valuable insights into why ALF develops after severe APAP overdose and will assist in addressing this unmet clinical need.


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 = -$44,622 )
2025	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	3/25/2025	NON-COMPETING CONTINUATION	-$10,435
2025	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/21/2025	NON-COMPETING CONTINUATION	-$26,836
2025	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	3/25/2025	NEW	-$7,351
														Subtotal = -$44,622

Issue Date FY: 2024 ( Subtotal = $37,271 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/18/2024	NON-COMPETING CONTINUATION	$35,991
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/30/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $37,271

Issue Date FY: 2023 ( Subtotal = $35,991 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/14/2023	NEW	$35,991
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	2/14/2023	NEW	$0
														Subtotal = $35,991

Grand Total All Awards = $28,640

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Senescent hepatocytes mediate reprogramming of immune cells in acute liver failure

Award Number: F31DK134197

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/15/2023

PERIOD OF PERFORMANCE END DATE: 04/01/2024

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