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The Immune Response After Drug Induced Hepatotoxicity

Award Number: R01DK125465
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: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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The Immune Response After Drug Induced Hepatotoxicity - PROJECT SUMMARY Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States and thus is an important clinical problem. Though the current antidote N-acetylcysteine (NAC) was developed in the 1970's and is effective if administered early, its efficacy decreases if given beyond 8 hours after an APAP overdose. In spite of the significant progress in understanding mechanisms of APAP-induced liver injury in the subsequent decades, no additional therapeutic approaches to complement NAC have been developed and translated to the clinic. Part of the problem is the delayed presentation of patients to the hospital, by which time the injury process is often in progress and any drugs including NAC targeting early processes may be of limited benefit. It is now recognized that the regenerative capacity of the liver subsequent to APAP-induced injury is a critical feature dictating patient prognosis. APAP induces a late innate immune reaction in response to cell injury, and our early studies in mice and humans indicated that immune cell infiltration facilitated removal of damaged cells and was helpful in regeneration and recovery. Our recently published data now indicate that guidance cues such as the protein netrin-1 function through the adenosine A2B receptor to suppress neutrophils and enhance macrophage infiltration into the necrotic area to facilitate liver regeneration and recovery after an APAP overdose. Based on recent information that neutrophil and macrophage phenotypes can shift cell functionality from pro-inflammatory to anti-inflammatory, we hypothesize that activation of the adenosine A2B receptor enhances immune-cell mediated liver recovery after APAP overdose and this could be an effective late-acting therapeutic approach against APAP-induced hepatotoxicity. This hypothesis will be tested by 1) Elucidating molecular mechanisms involved in macrophage recruitment and liver regeneration after activation of the adenosine A2B receptor and their facilitation of recovery after APAP overdose in vivo, 2) Examining the effects of pharmacological modulation as well as deficiency of the adenosine A2B receptor on APAP-induced liver injury in vivo, and 3) Explore the role of A2BAR agonists and the innate immune response after prolonged NAC and evaluate circulating monocyte markers from patients after APAP overdose. We have advanced early acting alternative therapies for APAP overdose such as 4-methylpyrazole (4MP) through pre- clinical animal experiments and volunteer safety studies to planning of a clinical trial. While 4MP functions to prevent APAP-induced injury and would be beneficial in patients with severe overdose, it is anticipated that results from the studies proposed here will provide novel insight into the A2B receptor as a putative target for a late acting therapeutic to complement 4MP and NAC in the clinic and improve outcomes after an APAP overdose.


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 = $306,900 )
2025	2025	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	5	12/23/2024	NON-COMPETING CONTINUATION	$306,900
														Subtotal = $306,900

Issue Date FY: 2024 ( Subtotal = $327,360 )
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	4	12/8/2023	NON-COMPETING CONTINUATION	$306,900
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	4	5/15/2024	NON-COMPETING CONTINUATION	$20,460
														Subtotal = $327,360

Issue Date FY: 2023 ( Subtotal = $341,000 )
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	3	1/24/2023	NON-COMPETING CONTINUATION	$341,000
														Subtotal = $341,000

Issue Date FY: 2022 ( Subtotal = $339,900 )
2022	2022	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/30/2022	NON-COMPETING CONTINUATION	$33,990
2022	2022	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/16/2021	NON-COMPETING CONTINUATION	$305,910
														Subtotal = $339,900

Issue Date FY: 2021 ( Subtotal = $338,800 )
2021	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/19/2021	NEW	$338,800
														Subtotal = $338,800

Grand Total All Awards = $1,653,960

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The Immune Response After Drug Induced Hepatotoxicity

Award Number: R01DK125465

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: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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