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Novel proteolytic mechanisms driving pathologic hepatic congestion in drug-induced hepatotoxicity

Award Number: R01DK135649
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: 05/11/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Novel proteolytic mechanisms driving pathologic hepatic congestion in drug-induced hepatotoxicity - Modified Project Summary/Abstract Section The summary/abstract did not require alteration The leading cause of acute liver injury and acute liver failure in the United States is hepatotoxicity caused by overdose of the pain medication acetaminophen (APAP). Even with available treatments (i.e., N-acetylcysteine), more than half of APAP overdose patients require costly hospitalization and antiquated standards to guide treatment. APAP overdose patients would benefit most from treatments that prevent the progression of simple hepatotoxicity to liver failure. Using robust experimental settings and results from acute liver failure patients, our team uncovered a novel pathway whereby macrophage elastase (MMP-12) prevents progression of hepatotoxicity to ALF by reducing excess production of the fibrinolytic enzyme plasmin. The current view is that plasmin production in the APAP-injured liver is controlled by standard proteins involved in blood clot lysis. However, our strong preliminary studies suggest that, in contrast to the current paradigm, hepatic plasmin generation is controlled locally by direct MMP-12-dependent proteolysis of the plasminogen zymogen. The central hypothesis framing these studies is macrophage elastase (MMP-12) prevents vascular damage and intrahepatic congestion after APAP overdose by cleaving plasminogen at a site that releases the anti-inflammatory factor angiostatin while preventing formation of active plasmin. Our approach includes genetically-modified mice with deficiency in components of the signaling pathway controlling MMP-12 expression, mice expressing plasminogen with an active site mutation that prevents plasmin activity, novel lipid nanoparticles to superimpose plasminogen deficiency in experimental APAP hepatotoxicity, and leading edge N-degradomics to pinpoint plasmin substrates in the injured liver. The established investigative team comprises experts in APAP-induced liver injury and repair, biochemistry/function of the fibrinolytic system, vascular pathology, leading-edge proteomic analysis, and experimental settings of liver disease. In our proposed studies we will: define the cellular and molecular mechanisms driving MMP-12 expression after acetaminophen overdose (Aim 1); determine the mechanisms whereby MMP-12 prevents pathologic vascular congestion in the acetaminophen-injured liver (Aim 2); and determine the role of plasmin(ogen) proteolytic and non-proteolytic functions in APAP-induced liver injury (Aim 3). The expected outcome of these Specific Aims is the discovery of a novel mechanistic link between leukocyte effector function (i.e., MMP-12 expression) and prevention of intrahepatic hyperfibrinolysis in the injured liver, including evidence of a novel molecular mechanism controlling plasmin generation. This could pinpoint mechanistic biomarkers to predict imminent hepatic vascular dysfunction in the injured liver and to uncover therapeutic modalities to prevent hepatic congestion after hepatotoxicant exposure. By virtue of separation from traditional regulation of fibrinolysis, this could greatly improve outcome in APAP overdose without increasing bleeding risk.


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 = $487,951 )
2026	2026	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 360	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/10/2026	NON-COMPETING CONTINUATION	$487,951
														Subtotal = $487,951

Issue Date FY: 2025 ( Subtotal = $444,931 )
2025	2025	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/20/2025	NON-COMPETING CONTINUATION	$444,931
														Subtotal = $444,931

Issue Date FY: 2024 ( Subtotal = $483,735 )
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/9/2024	NON-COMPETING CONTINUATION	$453,504
2024	2024	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/15/2024	NON-COMPETING CONTINUATION	$30,231
														Subtotal = $483,735

Issue Date FY: 2023 ( Subtotal = $497,939 )
2023	2023	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD RM 2	EAST LANSING	MI	48824	INGHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/10/2023	NEW	$497,939
														Subtotal = $497,939

Grand Total All Awards = $1,914,556

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Novel proteolytic mechanisms driving pathologic hepatic congestion in drug-induced hepatotoxicity

Award Number: R01DK135649

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: 05/11/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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