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Liver Pathobiology: insights through the lens of rare diseases

Award Number: R01DK131033
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: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Liver Pathobiology: insights through the lens of rare diseases - PROJECT SUMMARY/ABSTRACT Chronic liver disease (CLD) is a major global health problem that affects over 1 billion people globally and leads up to 2 million deaths annually. Chronic liver injury is typically silent, but when persistent may lead to liver fibrosis, which can progress to cirrhosis and clinically significant portal hypertension complications (such as ascites, esophageal variceal hemorrhage, and hepatic encephalopathy). These clinical signs are the most common cause of mortality from CLD, and for which liver transplantation is the only available curative intervention. Since the demands for liver transplantation still far exceeds the supply of available donor organs, end-stage liver disease represents the 11th leading cause of death worldwide. Hence, advances in the molecular understanding of liver injury and pathobiology are critical to develop novel diagnostic, prognostic and therapeutic tools, with the goal to decrease the demand for liver transplantation in the future. For several years, my research has focused on the study of individuals with rare liver phenotypes of unknown etiology as a roadmap to uncover novel molecular mechanism(s) underlying liver pathology that may be relevant to the pathogenesis and treatment of common liver diseases. As part of this ongoing effort, we recently found that recessive genotypes in a small GTPase, named GIMAP5, cause liver sinusoidal endothelial cell capillarization and liver dysfunction. Taking advantage of an available Gimap5 loss-of-function (LOF) mutant mouse model, which recapitulates the sinusoidal endothelial cell capillarization phenotype seen in Gimap5-deficient humans, we demonstrate that Gimap5 is expressed in liver endothelial cells and its selective deletion in these cells lead to liver sinusoidal endothelial cell (LSEC) de-differentiation into capillarized endothelial cells (CECs). Furthermore, single cell RNA- sequencing analysis of sorted liver endothelial cells isolated from Gimap5-deficient and Gimap5-sufficient mice shows a near complete replacement of healthy LSECs by CECs. Importantly, LSEC de-differentiation into CECs is an event described in liver fibrosis, in general, independent of the etiology of liver injury. Here, we propose to define the key contributors in maintaining LSEC identity and preventing hepatic sinusoidal endothelial cell capillarization through the completion of the following two aims: (1) identify the cell extrinsic cues that signal through GIMAP5 to maintain LSEC identity; and (2) characterize the Gimap5 signal transduction pathway in liver endothelial cells. Collectively, the knowledge generated by this proposal has the potential to identify novel therapeutic targets to revert CECs into healthy LSECs, and this way develop new non-invasive therapies for liver fibrosis, cirrhosis and portal hypertension, which represent a major unmet medical need.


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: 2027 ( Subtotal = $0 )
2027	2026	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	000	5	10/22/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $501,886 )
2026	2026	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	001	5	8/7/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$501,886
2026	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/30/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $501,886

Issue Date FY: 2025 ( Subtotal = $491,654 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	4/23/2025	NON-COMPETING CONTINUATION	$491,654
														Subtotal = $491,654

Issue Date FY: 2024 ( Subtotal = $471,988 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/7/2024	NON-COMPETING CONTINUATION	$471,988
														Subtotal = $471,988

Issue Date FY: 2023 ( Subtotal = $491,654 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/2/2023	NON-COMPETING CONTINUATION	$491,654
														Subtotal = $491,654

Issue Date FY: 2022 ( Subtotal = $434,898 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/6/2022	NEW	$434,898
														Subtotal = $434,898

Grand Total All Awards = $2,392,080

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Liver Pathobiology: insights through the lens of rare diseases

Award Number: R01DK131033

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: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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