Novel strategies to accelerate repair of drug-induced hepatotoxicity

Active Project Grant Awarded Last action

Award ID
R01DK136733
Recipient
Awarding agency
Obligated
$4,516,796

Award facts

Completion date 69% complete
Place of performance
East Lansing, MI 48824, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Acute liver injury caused by overdose of the pain medication acetaminophen (apap) is a leading cause of acute liver injury in the united states. In many cases, a failure of liver repair causes acute liver injury to persist and this can progress to acute liver failure (ALF). Acute liver injury and ALF have a poor prognosis and little therapeutic options beyond intensive care. Over the past decade, several studies have highlighted how changes in the hemostatic system are connected to the progression of ALF. For example, an unbalance in the platelet adhesive protein VON willebrand factor (VWF) and its primary regulatory enzyme ADAMTS13 have been identified as unique indicators of increased risk for liver transplant and death in patients with ALF. Our published studies indicate that VWF inhibits repair of the apap-injured liver. Strong preliminary results using mice with deficiencies in VWF or ADAMTS13, leading-edge VWF-targeted therapeutics, and human ALF samples suggest that VWF inhibits the resolution of apap-induced liver injury. Based on our published and preliminary studies, our central hypothesis is that hepatic VWF deposition inhibits the resolution of apap- induced liver injury through formation of intrahepatic VWF-platelet microthrombi. Our approach includes genetically-modified mice, VWF-targeted molecules in clinical development, novel molecules designed to hold VWF in a resting state, and novel VWF-targeted thrombolytic drugs. These studies are closely aligned with creative analyses in which we seek to uncover VWF-focused biomarkers as novel biomarkers of liver repair and outcome in samples from a large, well-characterized cohort provided by the ALF study group. The investigative team represents an optimal pairing of experts on hemostasis and liver disease, experts on VWF and thrombolysis, and highly collaborative physician-scientists, increasing the impact of our studies and potential for translation. Our proposed studies will determine the role of ADAMTS13 and VWF multimer size in apap-induced liver injury and repair (aim 1), determine the mechanisms linking VWF to inhibition liver repair after apap challenge (aim 2), and identify strategies to accelerate degradation of pathologic VWF deposits to enhance repair of the apap-injured liver (aim 3). The expected outcome of these specific aims is the discovery of novel mechanisms whereby VWF inhibits repair of the injured liver. This outcome would make a significant impact on the field because IT would deliver novel mechanistic details for clinical associations between VWF and poor outcome in acute liver injury. The proposed studies are transformative and anticipated to deliver clinically applicable strategies to accelerate repair of the liver, owing to a strong combination of experimental and translational science backed by a team with clinical and basic research expertise.

Transactions

Action Obligated Date
Amendment $559,602
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Amendment $537,217
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Amendment $587,852
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Original award $587,852
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Subawards

Subrecipient Amount Awarded
Universitair Medisch Centrum Utrecht Dr. Schiffelers (UMC Utrecht) will serve as Co-Investigator and mentor to graduate student Hinde el Otmani who is primarily responsible for production of the… $30,000
Universitair Medisch Centrum Groningen (Umcg) We will measure 5 analytes by enzyme-linked immunosorbent assay (plasmin-cleaved VWF, active VWF, ADAMTS13-cleaved VWF, VWF propeptide, and VWF antigen), one by… $62,817
Universitair Medisch Centrum Utrecht Dr. Schiffelers (UMC Utrecht) will serve as Co-Investigator and mentor to graduate student Hinde el Otmani who is primarily responsible for production of the… $30,000

Quick answers

Who received award R01DK136733?

R01DK136733 was awarded to Michigan State University by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on July 1, 2023.

How much is award R01DK136733 worth?

$4,516,796 has been obligated on R01DK136733.

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