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Refining Physiologic Mechanisms for Intravascular Triglyceride Metabolism

Award Number: R01HL087228
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2007
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Refining Physiologic Mechanisms for Intravascular Triglyceride Metabolism - During the second cycle of this Multiple Principal Investigator R01 grant, we investigated lipoprotein lipase (LPL) and GPIHBP1 (the endothelial cell protein that shuttles LPL to the capillary lumen) and the roles of both proteins in the lipolytic processing of triglyceride-rich lipoproteins (TRLs). We were productive, publishing >20 manuscripts, all in top-tier journals. Of note, we discovered a new human disease—chylomicronemia from GPIHBP1 autoantibodies. We defined the pathophysiology of that disease and with our collaborators showed that the disease can be treated quite effectively with rituximab, resulting in disappearance of autoantibodies and normalization of plasma triglyceride levels. We also explored basic physiologic mechanisms for intravascular lipolysis. We showed that LPL is active as a monomer, dispelling decades-old dogma that LPL is a homodimer. We showed that GPIHBP1 preserves the structure and activity of LPL's hydrolase domain. We solved the atomic structure of the LPL–GPIHBP1 complex, which provided insights into how GPIHBP1 stabilizes LPL and how specific LPL and GPIHBP1 mutations cause human disease. For the third grant cycle, we have two specific aims. The first is to test the hypothesis that GPIHBP1's acidic domain is crucial for the movement of LPL–GPIHBP1 complexes from the abluminal to the luminal plasma membrane (PM) of capillary endothelial cells. We recently created gene-edited mice expressing a mutant GPIHBP1 lacking the acidic domain. GPIHBP1's LU domain was unaltered; hence, the mutant GPIHBP1 was able to bind LPL. Unexpectedly, the absence of the acidic domain impeded trafficking of the GPIHBP1–LPL complex from the abluminal PM of endothelial cells to the capillary lumen. We suspect that the movement of LPL–GPIHBP1 complexes away from the abluminal plasma membrane was impeded by persistent electrostatic interactions between the GPIHBP1-bound LPL and adjacent heparan sulfate proteoglycans (HSPGs). Using a combination of surface plasmon resonance studies and in vivo GPIHBP1 transport studies, we will test the hypothesis that a crucial function of GPIHBP1's acidic domain is to disrupt interactions between GPIHBP1-bound LPL and nearby HSPGs along the abluminal plasma membrane, thereby freeing LPL to move across endothelial cells to the capillary lumen. Our second specific aim is to explore a recent discovery, using advanced microscopy, that some of the LPL that is transported into capillaries by GPIHBP1 subsequently detaches from GPIHBP1 and enters the HSPG-rich glycocalyx. Taking advantage of super-resolution confocal microscopy, electron microscopy, and NanoSIMS imaging, we will characterize GPIHBP1-bound and glycocalyx-bound pools of LPL along capillary endothelial cells. We will also examine the relevance of the glycocalyx-bound LPL to TRL margination along capillaries and TRL processing. Finally, we will develop the tools required to test the relevance of glycocalyx LPL to human disease. We are ideally positioned, with all of the reagents, experimental approaches, and expert collaborators, to address our specific aims. We anticipate that our studies will transform textbook models of intravascular triglyceride metabolism.e metabolism.


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 = -$109,442 )
2027	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	18	10/20/2026	NON-COMPETING CONTINUATION	-$109,442
														Subtotal = -$109,442

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	18	6/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $572,094 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	18	8/15/2024	NON-COMPETING CONTINUATION	$572,094
														Subtotal = $572,094

Issue Date FY: 2023 ( Subtotal = $589,778 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	001	17	5/18/2023	NON-COMPETING CONTINUATION	$583,769
2023	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	14	11/23/2022	NON-COMPETING CONTINUATION	$6,009
														Subtotal = $589,778

Issue Date FY: 2022 ( Subtotal = $583,769 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	002	16	5/9/2022	NON-COMPETING CONTINUATION	$583,769
2022	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	001	15	4/13/2022	COMPETING CONTINUATION	$124,833
2022	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	14	4/13/2022	NON-COMPETING CONTINUATION	-$124,833
														Subtotal = $583,769

Issue Date FY: 2021 ( Subtotal = $583,769 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	001	15	8/1/2021	COMPETING CONTINUATION	$583,769
2021	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cardiovascular Diseases Research	000	14	7/29/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $583,769

Issue Date FY: 2020 ( Subtotal = $458,851 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	14	4/3/2020	NON-COMPETING CONTINUATION	$458,851
														Subtotal = $458,851

Issue Date FY: 2019 ( Subtotal = $458,851 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	13	4/10/2019	NON-COMPETING CONTINUATION	$458,851
														Subtotal = $458,851

Issue Date FY: 2018 ( Subtotal = $458,116 )
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	002	12	7/7/2018	NON-COMPETING CONTINUATION	$9,165
2018	2018	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	12	3/23/2018	NON-COMPETING CONTINUATION	$448,951
2018	2016	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	10	11/21/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $458,116

Issue Date FY: 2017 ( Subtotal = $455,909 )
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	11	9/13/2017	COMPETING CONTINUATION	$2,941
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	11	7/19/2017	COMPETING CONTINUATION	$452,968
														Subtotal = $455,909

Issue Date FY: 2016 ( Subtotal = $385,000 )
2016	2016	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	10	12/15/2015	EXTENSION WITH OR WITHOUT FUNDS	$379,224
2016	2016	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	10	2/6/2016	EXTENSION WITH OR WITHOUT FUNDS	$5,776
														Subtotal = $385,000

Issue Date FY: 2015 ( Subtotal = $379,224 )
2015	2015	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	9	12/3/2014	NON-COMPETING CONTINUATION	$346,500
2015	2015	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	9	3/10/2015	NON-COMPETING CONTINUATION	$32,724
														Subtotal = $379,224

Issue Date FY: 2014 ( Subtotal = $377,300 )
2014	2014	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	8	4/2/2014	NON-COMPETING CONTINUATION	$30,800
2014	2014	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	8	12/5/2013	NON-COMPETING CONTINUATION	$346,500
														Subtotal = $377,300

Issue Date FY: 2013 ( Subtotal = $366,520 )
2013	2013	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	7	12/5/2012	NON-COMPETING CONTINUATION	$346,500
2013	2013	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	001	7	6/24/2013	NON-COMPETING CONTINUATION	$20,020
														Subtotal = $366,520

Issue Date FY: 2012 ( Subtotal = $398,500 )
2012	2012	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	6	12/19/2011	COMPETING CONTINUATION	$398,500
														Subtotal = $398,500

Issue Date FY: 2011 ( Subtotal = $347,250 )
2011	2011	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	5	2/8/2011	NON-COMPETING CONTINUATION	$347,250
														Subtotal = $347,250

Issue Date FY: 2010 ( Subtotal = $347,250 )
2010	2010	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	4	2/25/2010	NON-COMPETING CONTINUATION	$347,250
														Subtotal = $347,250

Issue Date FY: 2009 ( Subtotal = $347,250 )
2009	2009	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	3	3/11/2009	NON-COMPETING CONTINUATION	$347,250
														Subtotal = $347,250

Issue Date FY: 2008 ( Subtotal = $347,250 )
2008	2008	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cardiovascular Diseases Research	000	2	3/3/2008	NON-COMPETING CONTINUATION	$347,250
														Subtotal = $347,250

Issue Date FY: 2007 ( Subtotal = $360,500 ) (Continued on the next page)
Grand Total All Awards = $7,707,739

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Refining Physiologic Mechanisms for Intravascular Triglyceride Metabolism

Award Number: R01HL087228

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2007

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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