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Uncovering the role of GPR75 as an activator of fatty acid transporters in non-alcoholic fatty liver disease (NAFLD)

Award Number: R03TR004478
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Uncovering the role of GPR75 as an activator of fatty acid transporters in non-alcoholic fatty liver disease (NAFLD) - The prevalence of obesity is a global concern with nearly 2 in 5 adults (42.4%) in the US having obesity. Rapid and sustained increases in weight gain result in various obesity-driven complications and health outcomes including non- alcoholic fatty liver disease (NAFLD). Recently, several predicted loss of function variants of the understudied orphan G protein- coupled receptor (GPCR), GPR75 were identified to be associated with leanness and a protective phenotype against obesity in a world-wide multi-ethnic exome sequencing of over 640,000 individuals. Our group was instrumental in these studies and our proposal seeks to examine the role of GPR75 in obesity and NAFLD. Specifically, we hypothesize that the pairing of GPR75 to its high-affinity ligand, 20-HETE, a vasoactive and proinflammatory lipid, exacerbating diet-induced obesity, driving NAFL and nonalcoholic steatohepatitis (NASH) which is characterized by pronounced inflammation, cell damage and fibrosis. To test this hypothesis, we propose two specific aims. Aim 1 seeks to determine the degree to which the pairing of 20-HETE/GPR75 contributes to the pathogenesis of obesity-driven NAFLD/NASH. This aim will evaluate the severity of obesity, diabetes/insulin resistance and liver damage in mice deficient in GPR75 and exposed to elevations in 20-HETE and a high-fat diet feeding protocol across time. A novel water-soluble GPR75 receptor blocker, AAA, will be used to assess the dependency of the disease development and progression on 20-HETE-GPR75 pairing. Aim 2 looks to identify the cellular mechanism by which the 20-HETE-GPR75 pairing drives increases in fatty acid uptake and inflammation which contribute to NAFLD. Specifically, it will determine how the activation of GPR75 via 20-HETE stimulates the activity of the fatty acid transporter 2 (FATP2) in hepatocytes. We will also evaluate how the combination of 20-HETE and fatty acid influx drive various proinflammatory and profibrotic signals. This particular aim will also incorporate the use of AAA (GPR75 receptor blocker) and hepatocytes deficient in GPR75. The implications behind the proposed research are highly innovative as they will lay the foundation and fundamentals as we continue to learn more about the role of GPR75 in obesity and NAFLD/NASH. Our preliminary data strongly suggest that GPR75 is a druggable target with translational applications for the prevention and treatment of obesity and NAFLD/NASH, diseases that presently plague the global healthcare system. Therefore, we believe that this application fits strongly with the IDG’s initiative to support studies pertaining to poorly characterized GPCRS in human health and disease.


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 = $0 )
2025	2023	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Trans-NIH Research Support	000	1	5/5/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $164,000 )
2023	2023	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Trans-NIH Research Support	000	1	6/29/2023	NEW	$164,000
														Subtotal = $164,000

Grand Total All Awards = $164,000

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Uncovering the role of GPR75 as an activator of fatty acid transporters in non-alcoholic fatty liver disease (NAFLD)

Award Number: R03TR004478

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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