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Structure-Function Relationship Studies of the Plasma Lipid Transfer Proteins CETP and PLTP

Award Number: R01HL115153
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/23/2012
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Structure-Function Relationship Studies of the Plasma Lipid Transfer Proteins CETP and PLTP - Project Summary/Abstract Cholesteryl ester transfer protein (CETP) mediates the transfer of lipids, including cholesteryl esters (CEs), triglycerides (TGs) and phospholipids (PLs) between high-density lipoproteins (HDL), low- density lipoproteins (LDL), and very low-density lipoproteins (VLDL). An elevated level of LDL- cholesterol (LDL-C) and/or a low level of HDL-cholesterol (HDL-C) in human plasma are major risk factors for cardiovascular disease (CVD) and familial hyperlipidemia disease. Since increased CETP can reduce HDL-C concentration and since CETP deficiency is associated with elevated HDL-C levels, five CETP inhibitors, i.e. Torcetrapib, Anacetrapib, Dalcetrapib, Evacetrapib and Obicetrapib have been investigated in clinical trials for treating CVD. However, the fact that three inhibitors failed in large clinical trials reflects our knowledge is little concerning the molecular mechanisms of CETP- mediated lipid transfer among lipoproteins. In the last funding period, we discovered the CETP penetrated to HDL and LDL/VLDL, forming a tunnel for CE transfer between lipoproteins. In this period, we propose to test highlighted residues that play key roles in CE transfer. It can be difficult to investigate CETP mechanisms using structural methods as interaction with CETP can alter the size, shape, and composition of lipoproteins, especially HDL. Thus, we propose i) to study the mutated CETP in CE transfer by all-atom molecular dynamic (MD) simulation and our validated optimized negative-staining electron microscopy (OpNS-EM) protocol. In OpNS, the flash-fixation of lipoprotein particles preserves a near native-state conformation for direct visualization of individual molecular or macromolecular particles. ii) In the last period, we identified a CETP interface that binds to lipoprotein and patented antibodies as CETP inhibitors for treatment of CVD. In this period, we propose to validate the antibodies’ function in regulating plasma lipid levels in a rabbit dyslipidemia model. iii) To further understanding the CETP function in plasma phospholipid transfer, we propose to study the PLTP interaction with lipoprotein as PLTP has a similar sequence to CETP but a stronger function in phospholipid transfer among lipoproteins.


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 = -$736 )
2025	2021	THE REGENTS OF THE UNIVERSITY OF CALIFORNIA	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	000	9	4/24/2025	NON-COMPETING CONTINUATION	-$736
														Subtotal = -$736

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	000	9	11/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	000	9	10/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = -$1,012 )
2022	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	000	5	10/1/2021	EXTENSION WITH OR WITHOUT FUNDS	-$1,012
														Subtotal = -$1,012

Issue Date FY: 2021 ( Subtotal = $500,089 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	001	9	5/18/2021	NON-COMPETING CONTINUATION	$49,997
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	000	9	12/30/2020	NON-COMPETING CONTINUATION	$450,092
														Subtotal = $500,089

Issue Date FY: 2020 ( Subtotal = $492,699 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	001	8	1/23/2020	NON-COMPETING CONTINUATION	$24,620
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	000	8	12/11/2019	NON-COMPETING CONTINUATION	$468,079
														Subtotal = $492,699

Issue Date FY: 2019 ( Subtotal = $521,804 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	000	7	12/11/2018	NON-COMPETING CONTINUATION	$521,804
														Subtotal = $521,804

Issue Date FY: 2018 ( Subtotal = $499,318 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	005	6	2/16/2018	COMPETING CONTINUATION	$128
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	003	6	1/12/2018	COMPETING CONTINUATION	$498,306
2018	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	002	5	1/11/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
2018	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	004	5	2/16/2018	EXTENSION WITH OR WITHOUT FUNDS	-$128
2018	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	001	5	1/3/2018	EXTENSION WITH OR WITHOUT FUNDS	$506
2018	2015	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	000	4	1/3/2018	NON-COMPETING CONTINUATION	$506
														Subtotal = $499,318

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	003	5	9/28/2017	EXTENSION WITH OR WITHOUT FUNDS	-$548
2017	2016	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	001	5	11/4/2016	EXTENSION WITH OR WITHOUT FUNDS	$68,843
2017	2015	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	000	4	11/4/2016	NON-COMPETING CONTINUATION	-$68,843
2017	2015	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1 CYCLOTRON RD	BERKELEY	CA	94720	ALAMEDA	USA	Cardiovascular Diseases Research	002	4	9/28/2017	NON-COMPETING CONTINUATION	$548
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $376,858 )
2016	2016	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cardiovascular Diseases Research	000	5	6/17/2016	EXTENSION WITH OR WITHOUT FUNDS	$376,858
														Subtotal = $376,858

Issue Date FY: 2015 ( Subtotal = $371,204 )
2015	2015	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cardiovascular Diseases Research	000	4	6/5/2015	NON-COMPETING CONTINUATION	$371,204
														Subtotal = $371,204

Issue Date FY: 2014 ( Subtotal = $369,320 )
2014	2014	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cardiovascular Diseases Research	000	3	6/30/2014	NON-COMPETING CONTINUATION	$369,320
														Subtotal = $369,320

Issue Date FY: 2013 ( Subtotal = $358,768 )
2013	2013	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cardiovascular Diseases Research	000	2	6/19/2013	NON-COMPETING CONTINUATION	$358,768
														Subtotal = $358,768

Issue Date FY: 2012 ( Subtotal = $423,573 )
2012	2012	LAWRENCE BERKELEY LABORATORY	POST OFFICE BOX 528	BERKELEY	CA	94701	ALAMEDA	USA	Cardiovascular Diseases Research	000	1	7/23/2012	NEW	$423,573
														Subtotal = $423,573

Grand Total All Awards = $3,911,885

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Structure-Function Relationship Studies of the Plasma Lipid Transfer Proteins CETP and PLTP

Award Number: R01HL115153

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/23/2012

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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