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Probing Cardiovascular Actions of GLP-1 Using Nanoparticles

Award Number: R01HL130516
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2016
PERIOD OF PERFORMANCE END DATE: 04/30/2022

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Probing Cardiovascular Actions of GLP-1 Using Nanoparticles - Project Summary Hyperglycemia is the hallmark of type 2 diabetes (T2D) and accelerates the development of atherosclerosis, which, in turn, precedes the development of major cardiovascular complications. In people with T2D, cardiovascular disease significantly contributes to mortality, accounting for 65%-to-80% of T2D deaths. The development of pharmaceutical agents that lower glucose while also treating cardiovascular disease is therefore a priority. However, current cardiovascular agents (statins, fibrates, antihypertensives) are only moderately efficacious in T2D, partly because these agents incompletely address certain vascular abnormalities, such as inflammation, foam cell formation and leukocyte recruitment to the arterial wall. Therefore, more effective interventions are needed that treat both hyperglycemia and atherosclerosis. The goal of this proposal is to elucidate the molecular mechanisms of glucagon-like peptide-1 (GLP-1) in cardiovascular disease through the use of nanoparticle probes that target and image atherosclerosis. GLP-1 is an endogenous gut-derived hormone presently used in clinics in the form of peptide mimetics that provide glycemic control in patients with T2D. We and other investigators have demonstrated that GLP-1 exerts a multitude of effects on immune cells and has the potential to reduce atherosclerosis. We posit that GLP-1 may directly regulate immune cell behavior by activating its receptor, GLP-1R, thereby reducing monocyte recruitment to the plaque, potentiating macrophage and cholesterol exit, and resolving inflammation. In order to isolate glucose lowering and systemic effects of GLP-1 from its actions on immune cells in atherosclerosis, an effective drug delivery system would be required that favors accumulation of GLP-1 in lesional leukocytes. We propose to investigate locus-specific actions of GLP-1 with the use of engineered nanoparticles that will image lesional and blood leukocytes simultaneously delivering a payload of a GLP-1 mimetic within plaque. This technology activates the drug release in the plaque following the retention of MRI-visible nanoparticles facilitated by eat-me signals. The underlying mechanisms of the anti-atherogenic effects of GLP-1 will be evaluated by carrying out two specific aims: Specific aim 1 will determine the inflammatory and migratory phenotype of leukocytes that were targeted by nanoparticles or GLP-1 alone. Here we will assess acute effects of GLP-1 on immune cells. Specific aim 2 will define whether lipid or anti-inflammatory effects govern anti-atherogenicity of GLP-1. Here, we will investigate atherosclerosis inhibition depending on the locus of GLP-1 delivery following chronic treatment regimen. Organ-specific actions of GLP-1 will be explored using on-demand nanoparticle delivery via modern pegylation technologies. In sum, the significance of this proposal is that it addresses an urgent clinical need for improved treatment strategies targeting both hyperglycemia and atherosclerosis.


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: 2023 ( Subtotal = $0 )
2023	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	5	11/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $396,250 )
2020	2020	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	5	5/12/2020	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2019 ( Subtotal = $396,250 )
2019	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	4	4/12/2019	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2018 ( Subtotal = $367,000 )
2018	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	000	3	4/14/2018	NON-COMPETING CONTINUATION	$367,000
														Subtotal = $367,000

Issue Date FY: 2017 ( Subtotal = $396,250 )
2017	2017	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	001	2	5/10/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$396,250
2017	2017	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cardiovascular Diseases Research	003	2	6/9/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$283,514
2017	2016	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	1	5/9/2017	NEW	$0
2017	2016	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	002	1	6/9/2017	NEW	-$283,514
														Subtotal = $396,250

Issue Date FY: 2016 ( Subtotal = $385,000 )
2016	2016	UNIVERSITY OF MARYLAND BALTIMORE PROFESSIONAL SCHOOLS	220 ARCH ST OFFICE LEVEL 2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cardiovascular Diseases Research	000	1	3/11/2016	NEW	$385,000
														Subtotal = $385,000

Grand Total All Awards = $1,940,750

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Probing Cardiovascular Actions of GLP-1 Using Nanoparticles

Award Number: R01HL130516

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2016

PERIOD OF PERFORMANCE END DATE: 04/30/2022

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