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Investigation of the Molecular Mechanisms of Lipoprotein Lipase Inhibitors

Award Number: R01HL125654
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Investigation of the Molecular Mechanisms of Lipoprotein Lipase Inhibitors - Lipoprotein lipase (LPL) is a secreted lipase and the key enzyme in clearing triglycerides from circulating lipoproteins. Because elevated plasma triglycerides are an independent risk factor for cardiovascular disease, we seek ways to enhance LPL activity, which will lower plasma triglycerides. LPL activity is downregulated by a family of macromolecular inhibitors known as angiopoietin-like (ANGPTL) proteins. This family includes the LPL inhibitors ANGPTL3, ANGPTL4, and ANGPTL8. Loss-of-function mutations in the ANGPTLs results in increased LPL activity, and decreased serum triglycerides. Our objectives in this study are to better understand how the ANGPTLs associate with LPL, and with each other, so that we can target these interactions to prevent LPL inhibition. We will achieve these objectives in three specific aims. In Aim 1, we will build on our knowledge of the mechanisms used by ANGPTL3 and ANGPTL4 to inhibit LPL to identify new therapeutics that specifically block the inhibitor-LPL interaction. In Aim 2, we will use cryo-electron microscopy to solve structures of LPL bound to its inhibitors. Finally, in Aim 3, we will study the function of inhibitors within cells, and their transport out of cells. Successful completion of these aims will provide molecular details describing how LPL and its inhibitors come together, as well as new ways to block these interactions. Because of LPL's key role in regulating plasma triglyceride levels, these discoveries hold promise for new ways to prevent cardiovascular disease.


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 = $381,494 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	10	4/11/2024	NON-COMPETING CONTINUATION	$381,494
														Subtotal = $381,494

Issue Date FY: 2023 ( Subtotal = $381,840 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	9	5/15/2023	NON-COMPETING CONTINUATION	$381,840
														Subtotal = $381,840

Issue Date FY: 2022 ( Subtotal = $382,169 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	8	4/25/2022	NON-COMPETING CONTINUATION	$382,169
														Subtotal = $382,169

Issue Date FY: 2021 ( Subtotal = $382,482 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	002	7	4/19/2021	NON-COMPETING CONTINUATION	$382,482
2021	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	001	6	2/20/2021	COMPETING CONTINUATION	$70,263
2021	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	5	2/20/2021	NON-COMPETING CONTINUATION	-$70,263
														Subtotal = $382,482

Issue Date FY: 2020 ( Subtotal = $382,781 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	6	3/17/2020	COMPETING CONTINUATION	$382,781
														Subtotal = $382,781

Issue Date FY: 2019 ( Subtotal = $370,960 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	5	4/12/2019	NON-COMPETING CONTINUATION	$370,960
														Subtotal = $370,960

Issue Date FY: 2018 ( Subtotal = $370,960 )
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	4	4/19/2018	NON-COMPETING CONTINUATION	$370,960
														Subtotal = $370,960

Issue Date FY: 2017 ( Subtotal = $365,420 )
2017	2017	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	3	4/17/2017	NON-COMPETING CONTINUATION	$365,420
														Subtotal = $365,420

Issue Date FY: 2016 ( Subtotal = $370,960 )
2016	2016	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	2	4/22/2016	NON-COMPETING CONTINUATION	$370,960
														Subtotal = $370,960

Issue Date FY: 2015 ( Subtotal = $363,772 )
2015	2015	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Cardiovascular Diseases Research	000	1	6/30/2015	NEW	$363,772
														Subtotal = $363,772

Grand Total All Awards = $3,752,838

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Investigation of the Molecular Mechanisms of Lipoprotein Lipase Inhibitors

Award Number: R01HL125654

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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