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Impact of Dysfunctional HDL on Platelet Function and in vivo Thrombosis

Award Number: K08HL145075
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Impact of Dysfunctional HDL on Platelet Function and in vivo Thrombosis - PROJECT SUMMARY/ABSTRACT The studies outlined in this proposal will explore novel mechanisms by which dysfunctional high-density lipoprotein (HDL) impairs platelet function and promotes the prothrombotic phenotype and will test an innovative potential therapeutic strategy to reduce atherothrombosis. This proposal is for a Mentored Career Development Award by Dr. Wenliang Song in the Division of Cardiovascular Medicine of the Department of Medicine at Vanderbilt University. Dr. Song has a long-term career goal of being an independently funded physician-scientist focused on the role of lipid metabolism in cardiovascular disease. He has already invested heavily in this career path. He has extensive research background on lipoperoxidation and oxidative stress, platelet biology and rodent models of cardiovascular diseases. Recent evidence suggests that HDL function may be a better indicator than HDL cholesterol (HDL-C). Mounting evidence supports the concept that dysfunctional HDL, for example, oxidized HDL, loses its beneficial properties and actually contributes to the development of cardiovascular disease. Preliminary data in this proposal suggest that HDL from patients with Familial Hypercholesterolemia (FH) is enriched with peroxidation products, including malondialdehyde (MDA) and isolevuglandins(IsoLG), and is strikingly dysfunctional. Novel aldehyde scavengers, which targeted mitigate the adverse effects of reactive oxidative stress(ROS) without abrogating normal signaling of ROS, can reduce the peroxidation modification of the HDL and prevent formation of dysfunctional HDL. Previous studies suggest normal HDL can reduce agonist- stimulated platelet activation and aggregation, while oxidized HDL enhances platelet aggregation, yet the mechanisms are not clear. Interestingly, recent studies demonstrated that apoptosis also occurs in anucleate platelets, and apoptotic platelets accelerate in vivo arterial thrombosis formation. It is known that normal HDL is anti-apoptotic and oxidized HDL is pro-apoptotic in macrophages and endothelial cells, but no studies have ever investigated HDL’s effect on platelets apoptosis. Dr. Song hypothesizes that dysfunctional HDL, such as oxidized HDL and HDL from FH patient (FH-HDL), increase platelet activation in vivo leading to enhance thrombosis through inducing apoptosis. The effect of peroxidation modification of HDL, as well as FH-HDL, on platelet apoptosis and activity will be tested. Two in vivo thrombosis mouse models (acute and chronic) will also be used. Wild type, LDLr-/- and ApoA1-/-LDLr-/- mice will be used to mimic the FH condition, and to assess the contribution of HDL. Novel aldehyde scavengers will be used to protect HDL from dysfunction and rescue the phenotypes. This proposed research will provide novel insights into the impact of HDL on platelet biology and advance the field of HDL function in atherothrombosis. The principal investigator has assembled a multidisciplinary mentorship committee. He and his mentor have outlined a detailed well thought training plan. He will have 80% protected time for research. Vanderbilt offers an exceptional environment and strong institutional commitment to foster this candidate's transition to becoming an independent investigator.


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 = $0 )
2025	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	4	10/30/2024	NON-COMPETING CONTINUATION	$0
2025	2022	THE MIRIAM HOSPITAL	164 SUMMIT AVE	PROVIDENCE	RI	02906	PROVIDENCE	USA	Cardiovascular Diseases Research	001	5	2/6/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE MIRIAM HOSPITAL	164 SUMMIT AVE	PROVIDENCE	RI	02906	PROVIDENCE	USA	Cardiovascular Diseases Research	001	5	5/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$33,311
2024	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	4	5/10/2024	NON-COMPETING CONTINUATION	-$33,311
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $158,760 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	4	8/15/2022	NON-COMPETING CONTINUATION	$158,760
														Subtotal = $158,760

Issue Date FY: 2021 ( Subtotal = $158,760 )
2021	2021	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	3	8/25/2021	NON-COMPETING CONTINUATION	$158,760
														Subtotal = $158,760

Issue Date FY: 2020 ( Subtotal = $158,760 )
2020	2020	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	2	8/26/2020	NON-COMPETING CONTINUATION	$158,760
														Subtotal = $158,760

Issue Date FY: 2019 ( Subtotal = $158,760 )
2019	2019	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	1	3/14/2019	NEW	$158,760
														Subtotal = $158,760

Grand Total All Awards = $635,040

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Impact of Dysfunctional HDL on Platelet Function and in vivo Thrombosis

Award Number: K08HL145075

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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