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The role of IL-17 signaling in alcohol-induced HCC

Award Number: R01AA028550
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/06/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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The role of IL-17 signaling in alcohol-induced HCC - ABSTRACT: Hepatocellular carcinoma (HCC) is caused by hepatitis virus HBV/HCV, non-alcoholic steatohepatitis (NASH), and alcoholic liver disease (ALD), which typically progress from liver fibrosis, to cirrhosis and cancer. Our preliminary data demonstrate that genetic deletion of IL-17 signaling in steatotic hepatocytes significantly attenuates the development of HCC in ALD-injured mice, suggesting that IL-17 signaling is a target for anti- HCC therapy. Our central hypothesis is that IL-17 signaling regulates chemokine production, de novo lipogenesis, and TNFRI expression/turnover in steatotic hepatocytes. IL-17 signaling promotes ALD- and NASH-induced HCC via activation of TNF/TNFRI-SREBP1/2-DHCR7-cholesterol synthesis, and suppression of ARTS-1/NUC2-dependent TNFRI exocytosis. The goal of the study is to characterize the mechanism by which IL-17A/IL-17RA signaling regulates responses in metabolically injured hepatocytes, and to compare the pathways of IL-17 signaling in the experimental models of ALD- and NASH. Strategy: Responses to IL-17 signaling will be compared side-by side in ALD- and NASH-injured WT and hepatocyte-specific IL-17RA knockout mice with HCC. We determine if IL-17 signaling is similarly activated in NASH- and ALD-injured hepatocytes. We determine if blocking of IL-17 signaling in steatotic hepatocytes is sufficient to suppress HCC in the metabolically injured liver. Specifically, the role of IL-17 in the pathogenesis of DEN- or (Mup-uPA)- induced HCC in ALD- and NASH-injury will be studied in WT and hepatocyte-specific IL-17RA knockout mice (IL-17RAΔHep mice). Development of HCC, inflammation, steatosis and liver fibrosis will be across all groups of mice. Mutagenesis of WT and IL-17RA-deficient AFP+YAP+ HCC, and responses of steatotic hepatocytes to IL-17A will be characterized. Specifically, we determine if chemokine secretion, cholesterol synthesis are suppressed in metabolically injured IL-17RA-deficient hepatocytes (AIM1). We will test a novel hypothesis by which IL-17 signaling facilitates TNF/TNFRI-Caspase2-SP1-SREBP1/2-DHCR7-dependent cholesterol synthesis in steatotic hepatocytes via blocking ARTS-1-NUCB2-regulated TNFRI exocytosis (and possibly IL- 6, IL-1RII) thereby prolonging TNF (IL-6, IL-1) signaling and promoting alcohol-induced HCC (AIM2). Our findings will be translated into humans by characterization of IL-17RA-TNFRI-signaling pathways in archived human livers from HCC patients with ALD. We will test if therapeutic blocking of the key IL-17 signaling molecules (IL-17RA, TNFRI, ARTS-1, and DHCR7) specifically in hepatocytes using N-acetylgalactosamine (GalNAc)-conjugated antisense RNA oligonucleotides (ASOs) can effectively suppress steatosis, fibrosis, and HCC in WT mice with NASH and ALD (AIM3). If proven, hepatocyte-specific blocking of IL-17 signaling using GalNAc-ASOs can provide a new strategy for HCC treatment in ALD and NASH patients.


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: 2024 ( Subtotal = $464,520 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	001	4	5/30/2024	NON-COMPETING CONTINUATION	$464,520
2024	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	3	3/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $464,520

Issue Date FY: 2023 ( Subtotal = $464,520 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	3	5/31/2023	NON-COMPETING CONTINUATION	$464,520
														Subtotal = $464,520

Issue Date FY: 2022 ( Subtotal = $464,520 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	2	5/24/2022	NON-COMPETING CONTINUATION	$464,520
														Subtotal = $464,520

Issue Date FY: 2021 ( Subtotal = $464,520 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Alcohol Research Programs	000	1	8/6/2021	NEW	$464,520
														Subtotal = $464,520

Grand Total All Awards = $1,858,080

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The role of IL-17 signaling in alcohol-induced HCC

Award Number: R01AA028550

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/06/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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