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The role of AEG-1 in NASH and NASH-HCC

Award Number: R01DK107451
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: 07/25/2016
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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The role of AEG-1 in NASH and NASH-HCC - Summary Nonalcoholic steatohepatitis (NASH), the most common cause of chronic liver disease in the Western world and a major global health problem, leads to cirrhosis and hepatocellular carcinoma (HCC). The lack of an optimum therapy mandates better understanding of the molecular pathogenesis of NASH, identification of regulatory molecules and development of targeted therapeutic approaches. Studies, supported by previous cycle of this renewal application, unraveled a novel role of the oncogene Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) in promoting NASH. AEG-1 induces steatosis by inhibiting PPARα, hence fatty acid β-oxidation (FAO), and promoting translation of fatty acid synthesizing enzymes thus augmenting de novo lipogenesis (DNL). Additionally, AEG-1 activates NF-κB, a master regulator of inflammation. Thus AEG-1 plays a key role in NASH and NASH-HCC. We established the therapeutic efficacy of a hepatocyte-targeted nanoparticle delivering AEG-1 siRNA to inhibit HFD-induced NASH in mice. Macrophages play a pivotal role in the pathogenesis of NASH by regulating the functions of adipocytes and hepatocytes. We recently documented that AEG-1 plays a vital role in regulating macrophage activation and mice with deletion of AEG-1 in myeloid cells (AEG-1∆MAC) are profoundly resistant to N-nitrosodiethylamine (DEN)-induced inflammatory HCC. Our preliminary studies now document that AEG-1∆MAC mice are also resistant to HFD-induced NASH, and identify that a novel post-translational modification, cysteine palmitoylation, is required for protein translation and NF- κB activation functions of AEG-1. These observations allow us to hypothesize that macrophage AEG-1 promotes NASH by regulating adipocytes and hepatocytes, cysteine palmitoylation regulates AEG-1 functions which contribute to NASH development, and targeted inhibition of AEG-1 in macrophages and hepatocytes might be an effective therapeutic intervention for NASH. Experiments using relevant mouse models and human cells will be performed to address these hypotheses. Our proposed studies will unravel a novel role of AEG-1 in macrophages and a novel post-translational modification regulating AEG-1 function. Multiple clinical trials document efficacy of inhibiting expression of genes in the liver by RNA interference (RNAi) strategy in a variety of diseases thereby establishing potential application of this strategy to manage NASH in the clinics. Our proposed studies thus have important mechanistic and translational significance.


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 = $585,013 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	12/19/2024	NON-COMPETING CONTINUATION	$543,969
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	12/20/2024	SUPPLEMENT FOR EXPANSION	$41,044
														Subtotal = $585,013

Issue Date FY: 2024 ( Subtotal = $647,824 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	12/15/2023	SUPPLEMENT FOR EXPANSION	$70,363
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	5/15/2024	NON-COMPETING CONTINUATION	$36,092
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	12/12/2023	NON-COMPETING CONTINUATION	$541,369
														Subtotal = $647,824

Issue Date FY: 2023 ( Subtotal = $627,971 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	1/5/2023	NON-COMPETING CONTINUATION	$598,687
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	7/24/2023	SUPPLEMENT FOR EXPANSION	$29,319
2023	2019	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/21/2022	NON-COMPETING CONTINUATION	-$35
														Subtotal = $627,971

Issue Date FY: 2022 ( Subtotal = $623,536 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	3/24/2022	COMPETING CONTINUATION	$623,536
2022	2019	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/20/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $623,536

Issue Date FY: 2019 ( Subtotal = $342,705 )
2019	2019	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/21/2019	NON-COMPETING CONTINUATION	$342,705
														Subtotal = $342,705

Issue Date FY: 2018 ( Subtotal = $342,853 )
2018	2018	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/14/2018	NON-COMPETING CONTINUATION	$342,853
														Subtotal = $342,853

Issue Date FY: 2017 ( Subtotal = $346,488 )
2017	2017	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/27/2017	NON-COMPETING CONTINUATION	$346,488
														Subtotal = $346,488

Issue Date FY: 2016 ( Subtotal = $363,258 )
2016	2016	VIRGINIA COMMONWEALTH UNIVERSITY	327 WEST MAIN STREET	RICHMOND	VA	23284	RICHMOND CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/22/2016	NEW	$363,258
														Subtotal = $363,258

Grand Total All Awards = $3,879,648

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The role of AEG-1 in NASH and NASH-HCC

Award Number: R01DK107451

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: 07/25/2016

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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