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Leveraging arginase biology against metabolic disease

Award Number: R01DK131009
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: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Leveraging arginase biology against metabolic disease - ABSTRACT Intermittent fasting and caloric restriction are effective therapies against insulin resistance, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Yet, intensive lifestyle modifications are rarely sustainable. We made the provocative discovery that modulating systemic arginine status is sufficient to mimic the therapeutic effects of generalized caloric restriction on hepatic steatosis. This is clinically significant, because targeting arginine is a tractable pathway through which to treat metabolic disease. Accordingly, our long-term goal is to define the signaling cascades underlying adaptive hepatic glucose fasting, so that we can identify new therapies that leverage these pathways against NAFLD and NASH. Our unbiased transcriptomic screening in fasting mice identified a novel glucose fasting-induced effector: the amino acid hydrolase, arginase 2 (Arg2). Our new data demonstrate that forced hepatocyte-specific Arg2 expression reduces peripheral insulin resistance, hepatic steatosis, and inflammation in diabetic mice. Because hepatocyte arginine fate depends upon competition between Arg2 and the lysosomal arginine sensing machinery that dictate autophagic flux, and the pro-inflammatory enzyme, inducible nitric oxide synthase (iNOS), we hypothesize that fasting-induced hepatocyte Arg2 attenuates hepatic steatosis and inflammation by depleting hepatocyte arginine. To test this, we will: 1) examine pleiotropic therapeutic mechanisms of Arg2 action against insulin resistance and hepatic inflammation; 2) examine small-molecule and advanced biological therapeutics that mimic the therapeutic actions of Arg2 activation and 3) define their mechanistic underpinnings. Completing these aims will: 1) establish arginine status as a determinant of metabolic homeostasis; 2) identify how modulating arginase activity impacts cellular lysosomal sensing and its physiological outcomes; and 3) examine efficacy and mechanisms of novel therapies to NAFLD, NASH and insulin resistance.


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 = $440,154 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	7/24/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$440,154
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/23/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $440,154

Issue Date FY: 2024 ( Subtotal = $416,258 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/18/2024	NON-COMPETING CONTINUATION	$390,244
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	5/15/2024	NON-COMPETING CONTINUATION	$26,014
2024	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/17/2024	NEW	$0
														Subtotal = $416,258

Issue Date FY: 2023 ( Subtotal = $436,856 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/19/2023	NEW	$436,856
														Subtotal = $436,856

Grand Total All Awards = $1,293,268

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Leveraging arginase biology against metabolic disease

Award Number: R01DK131009

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: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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