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Lipid-Responsive E3 ubiquitin ligases in cholesterol metabolism and atheroscierosis

Award Number: R01HL136618
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2018
PERIOD OF PERFORMANCE END DATE: 10/31/2021

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Lipid-Responsive E3 ubiquitin ligases in cholesterol metabolism and atheroscierosis - Abstract Elucidating new control mechanisms for cholesterol homeostasis that affect atherosclerosis will advance our understanding of fundamental physiological processes and may suggest new opportunities for intervention in human metabolic disease. We propose to define the mechanism of action and physiological function of two new LXR-dependent regulatory circuits mediated by two novel E3 ubiquitin ligases. Molecular mechanisms mediating crosstalk between the SREBP-2 and LXR pathways are poorly understood. Using an RNA sequencing strategy to identify new LXR targets, we have uncovered two uncharacterized genes–Rnf145 and Rnf186–that may mediate critical pathways for crosstalk between LXR and SREBP signaling. Rnf145 and Rnf186 encode RING domain-containing proteins predicted to be E3 ubiquitin ligases; however, their ubiquitination targets and biological function are unknown. Our preliminary data have revealed that both RNF145 and RNF186 are previously unrecognized modulators of SREBP-2 signaling. Manipulation of Rnf145 and Rnf186 expression in mouse liver regulates SREBP-2-dependent gene expression and plasma cholesterol levels by distinct but complementary mechanisms. Based on these findings, we propose a series of molecular, cell biological and physiological studies to define the functions of RNF145 and RNF186 in cholesterol homeostasis and their contribution to LXR-SREBP crosstalk. Aim 1 is to elucidate the function and mechanism of action of RNF145 in lipid metabolism. Aim 2 is to elucidate the function and mechanism of action of RNF186 in lipid metabolism. Aim 3 is to determine the physiological importance of RNF145 and RNF186 for LXR- SREBP crosstalk and atherosclerosis.


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: 2022 ( Subtotal = -$30,291 )
2022	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	4/22/2022	NON-COMPETING CONTINUATION	-$30,291
														Subtotal = -$30,291

Issue Date FY: 2021 ( Subtotal = $514,800 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	4	5/18/2021	NON-COMPETING CONTINUATION	$51,480
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	11/20/2020	NON-COMPETING CONTINUATION	$463,320
														Subtotal = $514,800

Issue Date FY: 2020 ( Subtotal = $514,800 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	3	1/23/2020	NON-COMPETING CONTINUATION	$25,740
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	11/25/2019	NON-COMPETING CONTINUATION	$489,060
														Subtotal = $514,800

Issue Date FY: 2019 ( Subtotal = $514,800 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	12/11/2018	NON-COMPETING CONTINUATION	$514,800
														Subtotal = $514,800

Issue Date FY: 2018 ( Subtotal = $902,685 )
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	1	12/20/2017	NEW	$512,875
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	1	9/14/2018	SUPPLEMENT FOR EXPANSION	$389,810
														Subtotal = $902,685

Grand Total All Awards = $2,416,794

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Lipid-Responsive E3 ubiquitin ligases in cholesterol metabolism and atheroscierosis

Award Number: R01HL136618

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2018

PERIOD OF PERFORMANCE END DATE: 10/31/2021

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