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Soluble epoxide hydrolase: assessment of in vivo activity and regulation by gut microbiota

Award Number: R01HL146570
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/24/2021
PERIOD OF PERFORMANCE END DATE: 02/25/2026

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Soluble epoxide hydrolase: assessment of in vivo activity and regulation by gut microbiota - Epoxyeicosatrienoic acids (EETs) are lipid mediators with beneficial effects on metabolic and cardiovascular (CV) health. EETs and other FFA epoxides are quickly metabolized to biologically less active diols by soluble epoxide hydrolase (sEH). Inhibition of sEH, which increases EETs, improves metabolic and CV health and is proposed as an effective strategy to treat diabetes and CV diseases. Despite its importance to health, how sEH is regulated in vivo is poorly understood, particularly in humans where sEH is difficult to study, largely due to limited access to individual tissues where sEH is expressed or lack of appropriate tools to assess sEH activity. sEH activity is often inferred in human studies by measuring FFA epoxide-diol ratios in the blood. As many as 15 FFA epoxide-diol pairs can be measured in blood. We recently developed a new method to estimate sEH activity in vivo, which combines metabolomic determination and simultaneous analysis of all measurable epoxide-diol pairs. This method⎯Simultaneous Analysis of Multiple Indices (SAMI)⎯markedly increases the power to detect changes (or group differences) in sEH activity. This is important, especially in human studies, as increased power allows detection of treatment effects with smaller sample sizes, reducing cost. One objective of this proposal is to evaluate the performance of our new metabolomic approach, SAMI, in detecting changes in sEH activity or EET metabolism under various conditions in animals, before it can be widely applied to human studies. Using SAMI, our recent study showed that sEH activity decreased profoundly after a meal in rats. Interestingly, this effect was completely abolished in animals with gut bacteria depleted by antibiotic treatment, suggesting that gut bacteria may be involved in the postprandial effect. Our preliminary data suggest the intriguing possibility that lithocholic acid (LCA), a secondary bile acid produced by gut bacteria, may be an endogenous inhibitor of sEH, mediating the postprandial regulation of sEH activity. Another objective of this proposal is to validate this novel mechanism of postprandial sEH regulation involving LCA. Thus, the proposed studies will explore a novel mechanism for sEH regulation in vivo and evaluate the performance of our new method to assess sEH activity based on plasma oxylipins. Successful completion of the proposed studies would facilitate studies of sEH regulation in vivo in animals and humans and lead to new therapeutic targets or strategies in the treatment of diabetes or CV diseases.


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 = $400,325 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	2/1/2024	NON-COMPETING CONTINUATION	$367,646
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cardiovascular Diseases Research	001	4	6/21/2024	NON-COMPETING CONTINUATION	$32,679
														Subtotal = $400,325

Issue Date FY: 2023 ( Subtotal = $408,510 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	2/14/2023	NON-COMPETING CONTINUATION	$408,510
														Subtotal = $408,510

Issue Date FY: 2022 ( Subtotal = $408,530 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Cardiovascular Diseases Research	001	2	6/29/2022	NON-COMPETING CONTINUATION	$40,853
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	2/28/2022	NON-COMPETING CONTINUATION	$367,677
														Subtotal = $408,530

Issue Date FY: 2021 ( Subtotal = $424,792 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Cardiovascular Diseases Research	001	1	6/23/2021	NEW	$42,479
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	3/24/2021	NEW	$382,313
														Subtotal = $424,792

Grand Total All Awards = $1,642,157

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Soluble epoxide hydrolase: assessment of in vivo activity and regulation by gut microbiota

Award Number: R01HL146570

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/24/2021

PERIOD OF PERFORMANCE END DATE: 02/25/2026

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