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Principal Investigator: Andrei Maiseyeu
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2020
Award: $396,250
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Accounting><Acute><Address><Adult-Onset Diabetes Mellitus><Agonist><Alkynes><Anti-Hypertensive Agents><Anti-Hypertensive Drugs><Anti-Hypertensives><Anti-atherogenic><Anti-diabetic Agents><Antiatherogenic><Antidiabetic Agents><Antidiabetic Drugs><Antihypertensive Agents><Antihypertensive Drugs><Antihypertensives><Antiinflammatory Effect><Apoplexy><Arterial Fatty Streak><Arterial Fatty Streaks><Artificial nano particles><Artificial nanoparticles><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Attenuated><Avidity><Azides><Blood><Blood Glucose><Blood Pressure><Blood Reticuloendothelial System><Blood Sugar><Blood leukocyte><Blood monocyte><Body Weight decreased><Brain Vascular Accident><CD36><CD36 gene><Cadherins><Cardiac infarction><Cardiovascular><Cardiovascular Agents><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Drugs><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cessation of life><Chemotaxis><Cholesterol><Chronic><Clinic><Clinical><Clinical Research><Clinical Study><D-Glucose><Data><Death><Dendritic Cells><Detection><Development><Dextrose><Drug Delivery><Drug Delivery Systems><Drugs><Eating><Emigrations><Endocrine Gland Secretion><Event><Fibrates><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Foam Cells><Food Intake><Future><GLP-1><GP3B><GP4><GPIV><Gadolinium><Gd element><Gene Expression><Glucose><Goals><Heart Vascular><Hormones><Hyperglycemia><Hypertension><Hypotensive Agent><Hypotensive Drugs><Hypotensives><Image><Immune><Immunes><Inflammation><Inflammatory><Insulin Resistance><Intracellular Communication and Signaling><Investigators><Ketosis-Resistant Diabetes Mellitus><Label><Laboratories><Lesion><Leukocytes><Leukocytes Reticuloendothelial System><Lipids><Liver><MR Imaging><MR Tomography><MRI><Magnetic Resonance Imaging><Marrow leukocyte><Marrow monocyte><Maturity-Onset Diabetes Mellitus><Measurable><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Messenger RNA><Mice><Mice Mammals><Modality><Modeling><Modernization><Modification><Molecular><Mouse Homolog of NETRIN 1><Murine><Mus><Myeloid Cells><Myocardial Infarct><Myocardial Infarction><NETRIN 1-Like><NIDDM><NMR Imaging><NMR Tomography><NTN1><NTN1 gene><NTN1 gene product><NTN1L><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nuclear Magnetic Resonance Imaging><OGTT><Oral Glucose Tolerance Test><Organ><Pancreas><Pancreatic><Patients><Permeability><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phenotype><Public Health><Receptor Protein><Regression Analyses><Regression Analysis><Regression Diagnostics><Reporting><Research Personnel><Researchers><Risk Factors><SCARB3><Safety><Semaphorins><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Staining method><Stains><Statistical Regression><Stroke><Sum><T2 DM><T2D><T2DM><Technology><Testing><Therapeutic><Therapeutic Hormone><Transcript><Treatment Protocols><Treatment Regimen><Treatment Schedule><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Veiled Cells><Weight Loss><Weight Reduction><White Blood Cells><White Cell><Zeugmatography><adult onset diabetes><anti-diabetic><anti-diabetic drugs><anti-inflammatory effect><antidiabetic><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><base><biological signal transduction><blood lipid><body weight loss><brain attack><cardiac infarct><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><cell behavior><cellular behavior><cerebral vascular accident><cerebrovascular accident><circulatory system><coronary attack><coronary infarct><coronary infarction><developmental><diabetes mellitus therapy><diabetes therapy><diabetic><diabetic patient><drug/agent><effective intervention><engineered nano particle><engineered nanoparticle><flow cytophotometry><fluorophore><glucagon-like peptide 1><glycemic control><heart attack><heart infarct><heart infarction><hepatic body system><hepatic organ system><high blood pressure><hyperglycemic><hyperpiesia><hyperpiesis><hypertensive disease><imaging><improved><in vitro Assay><in vivo><insulin resistant><insulin sensitivity><ketosis resistant diabetes><laser capture microdissection><liraglutide><mRNA><macrophage><maturity onset diabetes><mimetics><monocyte><mortality><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><netrin-1><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><non-drug><nondrug><novel drug treatments><novel drugs><novel therapeutics><novel therapy><oxidized lipid><particle><peptide mimetic><peptide mimic><peptidomimetics><pleiotropic effect><pleiotropism><pleiotropy><receptor><recruit><targeted imaging><tool><treatment effect><treatment strategy><type 2 DM><type II DM><type two diabetes><vascular abnormality><vulnerable plaque><white blood cell><white blood corpuscle><wt-loss>