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Extracellular Matrix Regulates Hepatic Stellate Cell Activation and Fibrosis

Award Number: R01DK085252
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: 02/15/2011
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Extracellular Matrix Regulates Hepatic Stellate Cell Activation and Fibrosis - Project Summary Liver fibrosis is the consequence of chronic liver diseases, such as hepatitis B and C infection, alcohol- associated liver disease, and metabolic dysfunction-associated steatotic liver disease. Cirrhosis, the end stage of liver fibrosis, is the 11th leading cause of death in the US. To develop effective anti-fibrotics for liver fibrosis, we need a better understanding of the molecular basis of liver fibrosis. Prior to our study, hyaluronic acid (HA) was only known as a non-invasive biomarker for liver fibrosis. In the previous funding period, we determined that HA is actively synthesized by upregulated HA synthase 2 (HAS2) in activated hepatic stellate cells (HSCs) in liver fibrosis. HA synthesized by HAS2 is then converted to lower molecular weight (LMW)-HA, which activates CD44, TLR4, and Notch1 signaling, thereby activating HSCs for liver fibrosis progression. Although LMW-HA is critical for the development of fibrosis, the mechanisms of LMW-HA formation during liver fibrosis and HA-mediated fibrosis are still poorly understood. In the renewal application, we will characterize these mechanisms. The central hypothesis of this renewal application is that TMEM2, a newly identified hyaluronidase, mediates the production of extracellular LMW-HA that promotes liver fibrosis via fibrotic phenotypic changes in HSCs and liver sinusoidal endothelial cells (LSECs). Using cell-specific TMEM2 deletion mice, Aim 1 will determine the mechanism of extracellular HA catabolism by TMEM2. Aim 2 will determine the regulation of TMEM2 expression by focusing on two transcription factors, HIF1α and SOX4, in hypoxic and fibrotic environments. Because both HSCs and LSECs highly express CD44, a HA receptor, Aim 3 will determine the downstream effector pathways activated by HA and TMEM2 in HSCs and LSECs for liver fibrosis development. Aim 3 will also investigate whether the crosstalk between LSECs and HSCs is crucial for the HA-TMEM2-CD44-mediated HSC activation and fibrosis progression. We anticipate our results will provide valuable insights into the poorly understood mechanism of regulation of the profibrogenic activity of HA and its effect on HSCs and LSECs in the development of liver fibrosis. This will improve our understanding of the clinical value of HA, not only as a biomarker for liver fibrosis but also as a cause of liver fibrosis and a target for effective treatments.


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: 2026 ( Subtotal = $722,531 )
2026	2026	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	5/7/2026	NON-COMPETING CONTINUATION	$722,531
														Subtotal = $722,531

Issue Date FY: 2025 ( Subtotal = $722,531 )
2025	2025	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	5/21/2025	COMPETING CONTINUATION	$722,531
														Subtotal = $722,531

Issue Date FY: 2024 ( Subtotal = -$6,871 )
2024	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	2/23/2024	NON-COMPETING CONTINUATION	-$6,871
														Subtotal = -$6,871

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $393,750 )
2020	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	8/18/2020	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2019 ( Subtotal = $393,750 )
2019	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	8/19/2019	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2018 ( Subtotal = $393,750 )
2018	2018	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	7/31/2018	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2017 ( Subtotal = $393,750 )
2017	2017	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	9/18/2017	COMPETING CONTINUATION	$393,750
2017	2015	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/18/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $393,750

Issue Date FY: 2015 ( Subtotal = $369,750 )
2015	2015	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	2/7/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$369,750
														Subtotal = $369,750

Issue Date FY: 2014 ( Subtotal = $337,125 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/13/2014	NON-COMPETING CONTINUATION	$337,125
														Subtotal = $337,125

Issue Date FY: 2013 ( Subtotal = $325,326 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	5/15/2013	NON-COMPETING CONTINUATION	$21,913
2013	2013	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/18/2013	NON-COMPETING CONTINUATION	$303,413
														Subtotal = $325,326

Issue Date FY: 2012 ( Subtotal = $336,672 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/10/2012	NON-COMPETING CONTINUATION	$336,672
														Subtotal = $336,672

Issue Date FY: 2011 ( Subtotal = $386,250 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	7/11/2011	NEW	$50,212
2011	2011	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/7/2011	NEW	$336,038
														Subtotal = $386,250

Grand Total All Awards = $4,768,314

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Extracellular Matrix Regulates Hepatic Stellate Cell Activation and Fibrosis

Award Number: R01DK085252

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: 02/15/2011

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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