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Liver lobule zonation, hepatocellular carcinoma (HCC) and β-catenin mediated hepatitis B virus (HBV) biosynthesis

Award Number: R01CA238328
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Liver lobule zonation, hepatocellular carcinoma (HCC) and β-catenin mediated hepatitis B virus (HBV) biosynthesis - Project Summary and Relevance. Hepatitis B virus (HBV) infection is a worldwide health problem. It is estimated that there are 200 to 500 million HBV chronic carriers in the world for whom, to date, there is no reliable treatment. HBV causes both acute and chronic liver disease and is responsible for an estimated one million deaths annually from liver cirrhosis and primary hepatocellular carcinoma (HCC). Currently available therapies reduce viral loads but fail to resolve chronic HBV infections and hence require lifelong treatment. A major obstacle to the resolution of chronic HBV infections is the limited number of HBV targets that are suitable for the development of antiviral therapies. All the current antiviral therapies target the HBV reverse transcriptase/DNA polymerase, often leading to the development of drug-resistant variants. Curative therapies will require the identification of additional antiviral targets. Cellular gene products that make a significant contribution to HBV biosynthesis represent potential additional antiviral targets which alone or in combination with current HBV reverse transcriptase inhibitors may represent a potential curative therapy. One potential cellular gene target that might represent an HBV antiviral target is β-catenin, the terminal mediator of the Wnt/β-catenin signal transduction pathway which can be inhibited by the FDA-approved drug, Pyrvinium. Preliminary data indicate that β-catenin can activated HBV transcription and replication in cell culture and β-catenin activity correlates with viral biosynthesis in vivo in the HBV transgenic mouse model of chronic viral infection. Consequently, cell culture analysis will be performed to define the molecular mechanisms mediating β-catenin enhanced HBV transcription and replication. Characterization of inducible liver-specific β-catenin-null and APC-null (β-catenin activated) HBV transgenic mice will indicate the in vivo contribution of β-catenin to the restricted localization of viral biosynthesis to pericentral hepatocytes within the liver lobule and restricted viral expression within HCC tissue. Furthermore, treatment of HBV replicating cells and transgenic mice with Pyrvinium will indicate if an available FDA approved drug can modulate the Wnt/β-catenin signal transduction pathway and act as an antiviral therapy. Defining the role of the Wnt/β-catenin signal transduction pathway in determining the level of HBV biosynthesis may lead to the identification of cellular therapeutic targets that are amenable to the further development of novel modalities to resolve rather than simply treat chronic HBV infection.


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 = $347,483 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$18,289
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	5	11/2/2023	NON-COMPETING CONTINUATION	$329,194
														Subtotal = $347,483

Issue Date FY: 2023 ( Subtotal = $358,456 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	4	11/28/2022	NON-COMPETING CONTINUATION	$329,194
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	001	4	3/15/2023	NON-COMPETING CONTINUATION	$29,262
														Subtotal = $358,456

Issue Date FY: 2022 ( Subtotal = $358,456 )
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	3	11/8/2021	NON-COMPETING CONTINUATION	$329,193
2022	2022	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	001	3	5/19/2022	NON-COMPETING CONTINUATION	$29,263
														Subtotal = $358,456

Issue Date FY: 2021 ( Subtotal = $365,771 )
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	2	11/5/2020	NON-COMPETING CONTINUATION	$347,481
2021	2021	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	001	2	1/22/2021	NON-COMPETING CONTINUATION	$18,290
														Subtotal = $365,771

Issue Date FY: 2020 ( Subtotal = $365,771 )
2020	2020	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD RM 520	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	1	11/21/2019	NEW	$365,771
														Subtotal = $365,771

Grand Total All Awards = $1,795,937

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Liver lobule zonation, hepatocellular carcinoma (HCC) and β-catenin mediated hepatitis B virus (HBV) biosynthesis

Award Number: R01CA238328

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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