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Liquid biopsy for alcoholic hepatitis: diagnosis, prognosis and technology development

Award Number: U01AA021788
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT The long-term objective of this translational U01 is to define pathophysiologically informed and clinically relevant biomarkers based on the sphingolipidomic cargo of extracellular vesicles (EVs) that will serve for the diagnosis and prognosis of subjects with alcoholic hepatitis (AH). AH is the severest form of alcohol-induced liver disease with high mortality, high health care utilization, and the absence of effective therapies. Health care professionals are limited by the lack of predictive and prognostic biomarkers that could risk-stratify AH patients and individualize their therapy based on biomarker profiles. The current proposal links hepatocyte-derived sphinogolipid cargo on EVs to macrophage-mediated liver inflammation by proposing that sphingolipids on EVs from ethanol-damaged hepatocytes recruit macrophages in to the liver, resulting in liver injury and inflammation. Our preliminary data show that EVs are elevated in AH with the following features: i) EV sphingolipids are elevated in AH; ii) EV sphingolipid levels correlate with clinical parameters such as the international normalized ratio, bilirubin, and MELD score; iii) EVs activate proinflammatory macrophage effector responses via sphingolipid signaling; and iv) Hepatocyte-derived EVs can be detected via a novel nanoplasmon enhanced scattering (nPES) assay. This has led to the central hypothesis that circulating EV sphingolipid cargo is a pathogenically relevant biomarker for the diagnosis and prognosis of AH. Therefore, the goals of this proposal are to: i) develop an EV sphingolipidomic diagnostic signature for AH; ii) Demonstrate the ability of EV sphingolipidomics to predict mortality in AH; iii) Extend EV sphingolipidomics to a “proof-of-mechanism” assay for the beneficial effects observed in AH patients treated with therapeutic agents proposed in our linked complementary Clinical Trial Pilot U01 (RFA-AA-18-005); and iv) Develop a novel clinical test for the diagnosis of AH utilizing nPES technology to diagnose AH by detecting hepatocyte-derived EVs in plasma microsamples. First, we will determine the diagnostic performance of EV sphingolipids for AH in a single-site training cohort followed by a multi-site validation cohort. Second, we will directly test the hypothesis that EV sphingolipids can predict survival and response to a therapy that is expected to reduce the release of EVs from hepatocytes. Third, we will develop and validate a novel clinical assay for the diagnosis of AH. Thus, this multi-PI U01 grant application will yield a liquid biopsy biomarker for AH diagnosis and prognosis.


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 = -$1 )
2025	2022	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	10	11/1/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	10	1/24/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $245,768 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	001	10	6/14/2022	NON-COMPETING CONTINUATION	$245,768
2022	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	9	1/4/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $245,768

Issue Date FY: 2021 ( Subtotal = $245,768 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	001	9	6/29/2021	NON-COMPETING CONTINUATION	$245,768
2021	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	8	12/17/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $245,768

Issue Date FY: 2020 ( Subtotal = $245,768 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	001	8	6/12/2020	NON-COMPETING CONTINUATION	$245,768
2020	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	7	5/5/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $245,768

Issue Date FY: 2019 ( Subtotal = $247,878 )
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	003	7	7/18/2019	NON-COMPETING CONTINUATION	$247,878
2019	2018	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	001	6	10/29/2018	COMPETING CONTINUATION	$4,553
2019	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	002	6	10/31/2018	COMPETING CONTINUATION	$0
2019	2017	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	5	10/29/2018	SUPPLEMENT FOR EXPANSION	-$4,553
														Subtotal = $247,878

Issue Date FY: 2018 ( Subtotal = $250,000 )
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	6	9/22/2018	COMPETING CONTINUATION	$250,000
														Subtotal = $250,000

Issue Date FY: 2017 ( Subtotal = $625,003 )
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	001	5	7/25/2017	SUPPLEMENT FOR EXPANSION	$625,003
2017	2016	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	5	7/25/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $625,003

Issue Date FY: 2016 ( Subtotal = $625,003 )
2016	2016	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	5	6/24/2016	EXTENSION WITH OR WITHOUT FUNDS	$625,003
														Subtotal = $625,003

Issue Date FY: 2015 ( Subtotal = $591,431 )
2015	2015	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	4	6/26/2015	NON-COMPETING CONTINUATION	$591,431
														Subtotal = $591,431

Issue Date FY: 2014 ( Subtotal = $589,343 )
2014	2014	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	3	7/1/2014	NON-COMPETING CONTINUATION	$589,343
														Subtotal = $589,343

Issue Date FY: 2013 ( Subtotal = $557,044 )
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	2	7/2/2013	NON-COMPETING CONTINUATION	$522,045
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	001	2	9/4/2013	SUPPLEMENT FOR EXPANSION	$34,999
														Subtotal = $557,044

Issue Date FY: 2012 ( Subtotal = $484,683 )
2012	2012	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Alcohol Research Programs	000	1	9/17/2012	NEW	$484,683
														Subtotal = $484,683

Grand Total All Awards = $4,707,688

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Liquid biopsy for alcoholic hepatitis: diagnosis, prognosis and technology development

Award Number: U01AA021788

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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