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Managing Atherosclerosis by Modulating HDL Function

Award Number: R01HL118114
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2013
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Managing Atherosclerosis by Modulating HDL Function - PROJECT SUMMARY/ABSTRACT Atherosclerosis is the leading cause of human mortality worldwide. There has been a great interest in developing novel therapeutics for this disease that function via an orthogonal mechanism of action to currently available drugs. One promising strategy is to enhance the function of high-density lipoproteins (HDLs). HDLs facilitate reverse cholesterol transport (RCT) to transfer excess cholesterol from peripheral tissues to the liver for elimination. The proposed research, supported by strong recent progress, seeks to advance a novel supramolecular strategy for improving HDL function in vivo to combat atherosclerosis. The proposed studies build on the successes of our research program, funded by an NHLBI R01 grant over the past eight years. Despite substantial progress in the field of apolipoprotein mimetic peptides, including evaluation of several candidates in phase 1 and 2 human clinical trials, the inherent pharmacological shortcomings typically associated with linear peptides have been a major impediment to advancing HDL- modulating peptides through the clinic. Our proposed research seeks to develop a novel class of chemotypes that can recapitulate the functional attributes of helical lipoprotein mimetics, but without their inherent limitations. We have established that appropriately designed eight-residue self-assembling cyclic D,L-a-peptides are effective HDL modulating agents that can remodel human and mouse plasma HDLs and enhance cholesterol efflux from macrophage cells. These peptides specifically increase the level of pre-beta HDL particles (subspecies of HDLs considered to be the most anti-atherogenic), reduce LDL-cholesterol and triglyceride levels, and promote anti-inflammatory effects with concomitant prevention of atherosclerosis in mouse disease models. The abiotic structure of cyclic D,L-a-peptides overcomes many of the shortcomings typically associated with linear peptides, such as low serum/plasma stability and high production costs, among others. Specific aims 1 and 2 of the proposed research involve i) implementing a series of mechanism-based functional bioassays and biophysical assays to optimize and better characterize the mode of action of the lead compounds, and ii) establishing in vivo pharmacology, toxicology, and efficacy of selected cyclic peptides in two leading mouse models of atherosclerosis. Specific aim 3 of the proposed research is based on an unexpected, remarkable observation made in the course of our recent studies. We have discovered that trifluoroacetate (TFA), administered orally or parenterally, causes dose-dependent reductions in plasma cholesterol levels and prevents the development of atherosclerosis in vivo. The implications of this discovery are potentially broad because nearly all synthetic peptides, employed across diverse biological settings, contain TFA counterions resulting from purification by preparative HPLC. As such, the effects of TFA on cellular metabolism in vitro and in vivo must be characterized and understood. We propose a series of hypothesis-based in vitro and in vivo studies to define the mechanism and generality of the observed TFA-mediated anti-atherosclerosis effects.


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 = $773,645 )
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	12	4/23/2025	NON-COMPETING CONTINUATION	$707,820
2025	2025	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	001	12	6/4/2025	NON-COMPETING CONTINUATION	$65,825
														Subtotal = $773,645

Issue Date FY: 2024 ( Subtotal = $758,172 )
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	11	3/12/2024	NON-COMPETING CONTINUATION	$696,280
2024	2024	SCRIPPS RESEARCH INSTITUTE	10550 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	001	11	6/17/2024	NON-COMPETING CONTINUATION	$61,892
														Subtotal = $758,172

Issue Date FY: 2023 ( Subtotal = $773,645 )
2023	2023	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	10	3/24/2023	NON-COMPETING CONTINUATION	$773,645
														Subtotal = $773,645

Issue Date FY: 2022 ( Subtotal = $779,185 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	001	9	3/21/2022	COMPETING CONTINUATION	$779,185
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	003	9	8/31/2022	COMPETING CONTINUATION	$78,041
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	002	8	8/31/2022	NON-COMPETING CONTINUATION	-$78,041
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	8	3/17/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $779,185

Issue Date FY: 2021 ( Subtotal = $693,767 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	8	11/23/2020	NON-COMPETING CONTINUATION	$624,390
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	001	8	5/18/2021	NON-COMPETING CONTINUATION	$69,377
														Subtotal = $693,767

Issue Date FY: 2020 ( Subtotal = $693,767 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	7	12/5/2019	NON-COMPETING CONTINUATION	$659,080
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	001	7	1/24/2020	NON-COMPETING CONTINUATION	$34,687
														Subtotal = $693,767

Issue Date FY: 2019 ( Subtotal = $693,767 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	6	12/13/2018	NON-COMPETING CONTINUATION	$693,767
														Subtotal = $693,767

Issue Date FY: 2018 ( Subtotal = $729,767 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	5	12/27/2017	COMPETING CONTINUATION	$729,767
														Subtotal = $729,767

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	4	6/19/2017	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $673,750 )
2016	2016	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	4	4/22/2016	EXTENSION WITH OR WITHOUT FUNDS	$673,750
														Subtotal = $673,750

Issue Date FY: 2015 ( Subtotal = $653,301 )
2015	2015	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	3	3/27/2015	NON-COMPETING CONTINUATION	$653,301
														Subtotal = $653,301

Issue Date FY: 2014 ( Subtotal = $649,985 )
2014	2014	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	2	4/10/2014	NON-COMPETING CONTINUATION	$649,985
														Subtotal = $649,985

Issue Date FY: 2013 ( Subtotal = $631,414 )
2013	2013	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	5/28/2013	NEW	$631,414
														Subtotal = $631,414

Grand Total All Awards = $8,504,165

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Managing Atherosclerosis by Modulating HDL Function

Award Number: R01HL118114

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2013

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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