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Role of Ceramide in Hepatic Stellate Cell Activation and Liver Fibrosis

Award Number: K08DK114548
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 08/14/2023

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Role of Ceramide in Hepatic Stellate Cell Activation and Liver Fibrosis - PROJECT SUMMARY/ABSTRACT This is an application for a K08 award for Dr. Jennifer Y. Chen, a gastroenterologist and hepatologist at the Massachusetts General Hospital (MGH). Dr. Chen’s long-term career goal is to become an independently funded physician scientist, devoting more than 75% of her time to establish and maintain a basic science research program in hepatic fibrosis. This K08 award will provide Dr. Chen with the support necessary to achieve her short-term goals: 1) develop additional training in molecular biology, including investigating protein interactions and induction of stable gene expression; 2) gain expertise in genome-wide transcriptional analysis; 3) become proficient in transgenic mouse work and mouse models of hepatic fibrosis; and 4) produce the data and publication record necessary for a successful R01 application. In prior work, the candidate has developed a small molecule screen to identify compounds that inactivate hepatic stellate cells (HSCs), the primary cell type responsible for hepatic fibrosis. Through analysis of a hit, she identified that the sphingolipid ceramide can profoundly inhibit the activated effector phenotype of HSCs. Her work has identified a potential antifibrotic role for inhibition of acid ceramidase (aCDase), the enzyme responsible for ceramide metabolism. In this proposal, the candidate seeks to elucidate the mechanism by which ceramide accumulation inactivates HSCs and define the role of aCDase in fibrosis progression. The specific goals of the study are to: 1) determine how ceramide mediates HSC inactivation; and 2) define the impact of aCDase depletion and inhibition on fibrosis development in vivo. Under the first aim, the applicant will utilize a combination of techniques including immunoblotting, small molecule inhibition and activation, RNA interference, and expression of constitutively activated mutant proteins to understand how ceramide inactivates HSCs. Genome-wide expression analysis will be performed to elucidate transcriptional targets of ceramide. Under the second aim, the applicant will generate mice with a conditional fibroblast-specific deletion of aCDase, and will determine the extent to which they experience reduced fibrosis in two independent models of hepatic fibrosis. She will also determine the antifibrotic effects of a small molecule inhibitor of aCDase in vivo. As an integral part of this proposal, the candidate’s career development will be complemented by participation in advanced coursework and research seminars to develop expertise in molecular biology, genome-wide transcriptional analysis, and in vivo models of hepatic fibrosis. A formal mentorship committee and advisory team will provide supervision, guidance, and assistance for the candidate to achieve her goals. The research environment, which includes the MGH GI Unit, Harvard Fibrosis Network, Harvard College, Harvard Medical School, and the Harvard School of Public Health, will provide a rich, collaborative, and supportive atmosphere to ensure the candidate’s success. Through this award, the candidate will become an independent basic science investigator by contributing to the understanding of the role of the sphingolipid ceramide and its inactivation of HSCs ex vivo and in vivo.


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 = $0 )
2024	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	2/16/2024	NON-COMPETING CONTINUATION	$0
2024	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	12/7/2023	SUPPLEMENT FOR EXPANSION	$0
2024	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	4/21/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $321,300 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	9/14/2021	SUPPLEMENT FOR EXPANSION	$137,700
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	9/14/2021	NON-COMPETING CONTINUATION	$0
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/26/2021	NON-COMPETING CONTINUATION	$183,600
														Subtotal = $321,300

Issue Date FY: 2020 ( Subtotal = $183,600 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/23/2020	NON-COMPETING CONTINUATION	$183,600
														Subtotal = $183,600

Issue Date FY: 2019 ( Subtotal = $183,600 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	7/31/2019	NON-COMPETING CONTINUATION	$183,600
														Subtotal = $183,600

Issue Date FY: 2018 ( Subtotal = $183,600 )
2018	2018	BERKELEY MADONNA, INC.	1135 SPRUCE ST	BERKELEY	CA	94707	ALAMEDA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/27/2018	NON-COMPETING CONTINUATION	$183,600
														Subtotal = $183,600

Issue Date FY: 2017 ( Subtotal = $185,100 )
2017	2017	BERKELEY MADONNA, INC.	1135 SPRUCE ST	BERKELEY	CA	94707	ALAMEDA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/1/2017	NEW	$185,100
														Subtotal = $185,100

Grand Total All Awards = $1,057,200

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Role of Ceramide in Hepatic Stellate Cell Activation and Liver Fibrosis

Award Number: K08DK114548

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 08/14/2023

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