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Principal Investigator: Hana Totary-Jain
Organization: UNIVERSITY OF SOUTH FLORIDA
Fiscal Year: 2024
Award: $476,323
Funding agency: National Heart Lung and Blood Institute
Atherosclerotic cardiovascular disease (CVD) represents a serious affliction affecting millions globally. Despite
recent advances in pharmacological and percutaneous interventions, CVD remains the leading cause of death
and disability in the world. One of the main therapeutic challenges facing atherosclerotic CVD is the delivery of
therapies to the atherosclerotic plaque that target the specific cells which contribute to its formation, while
protecting the endothelium. Vascular endothelial cells provide crucial protection against lipid uptake,
inflammation and thrombosis. We hypothesize that cell-selective therapy that inhibits infiltration of inflammatory
cells and proliferation of vascular smooth muscle cells, while protecting endothelia cell function will be effective
in combating CVD and thrombosis. To achieve this goal, we will develop a novel miRNA switch that combines
synthetically modified mRNA with miRNA target site. As a delivery platform we will utilize the cationic amphipathic
cell-penetrating peptide that forms a self-assembled, compacted, nanoparticle when mixed with synthetic mRNA.
Moreover, to increase the targeting of inflammation in the atherosclerotic plaque, we will combine the miRNA
switch together with siRNA targeting IL1-β to generate nanoparticles using the same cationic amphipathic cell-
penetrating peptide. In two specific aims, we will test 1) the efficacy of this cell-selective nanotherapy to inhibit
atherosclerosis and restenosis after percutaneous intervention, while protecting EC to reduce thrombosis; and
2) the translational potential of the miRNA switch nanotherapy in viable, isolated human coronary arteries.
Completion of the aims will provide the foundation for the development of a novel category of biological drugs
that can accommodate the advent of personalized medicine and will advance the treatment of cardiovascular
disease.
Terms: <Ad vector><Adenoviral Vector><Adenovirus Vector><Affect><Animal Model><Animal Models and Related Studies><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Arterial Fatty Streak><Arterial Fatty Streaks><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Beta Proprotein Interleukin 1><Biological><Blood Vessels><CDK Inhibitor Protein><CDK inhibitor p27><CDKI Protein><CDKN1B protein><CDKN4 protein><Cannulations><Cardiac artery><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Carotid Arteries><Categories><Cause of Death><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Clinical><Clinical Research><Clinical Study><Common Rat Strains><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Coronary artery><Cyclin Kinase Inhibitor><Cyclin-Dependent Kinase Inhibitor><Cyclin-Dependent Kinase Inhibitor p27><Death><Development><Domestic Rabbit><Drugs><Dysfunction><Endothelial Cells><Endothelium><Epidemic><Event><Exhibits><Foundations><Functional disorder><Goals><Heart><Heart Vascular><Heart artery><Human><Hypercoagulability><Hyperplasia><Hyperplastic><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><Incidence><Infection><Inflammation><Inflammatory Infiltrate><Injury><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Intervention><Intervention Strategies><Isolated Perfusion><Isolation Perfusion><Isolation Perfusion Therapy><Kip1 protein><Knock-out><Knockout><Leiomyocyte><Lipids><Medication><Messenger RNA><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modeling><Modern Man><Murine><Mus><Oryctolagus cuniculus><Penetration><Peptides><Pharmaceutical Preparations><Physiology><Physiopathology><Preinterleukin 1 Beta><Proteins><Rabbits><Rabbits Mammals><Rat><Rats Mammals><Rattus><Recurrence><Recurrent><Regional Perfusion><Resistance><Safety><Short interfering RNA><Site><Small Interfering RNA><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Subcellular Process><Technology><Testing><Therapeutic><Thrombophilia><Thrombosis><Time><Toxic effect><Toxicities><Translating><UTRs><Untranslated Regions><Vascular Endothelial Cell><Vascular Smooth Muscle><Venous><adeno vector><adenovector><atheromatosis><atherosclerosis plaque><atherosclerotic coronary disease><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><biologic><cardiovascular disorder><circulatory system><coronary arterial disease><cyclin-dependent kinase inhibitor 1B><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><design><designing><determine efficacy><developmental><disability><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><endonuclease><evaluate efficacy><ex vivo perfusion><examine efficacy><femoral artery><healing><human tissue><injuries><interventional strategy><mRNA><miRNA><miRNAs><model of animal><mouse model><murine model><nano particle><nano switch><nano therapy><nano-sized particle><nanoparticle><nanosized particle><nanoswitch><nanotherapeutic><nanotherapy><new approaches><novel><novel approaches><novel strategies><novel strategy><overexpress><overexpression><p27 Kip1 protein><p27 protein><p27-Kip1><p27Kip1 protein><pathophysiology><personalization of treatment><personalized medicine><personalized therapy><personalized treatment><pharmacologic><pre-clinical study><preclinical study><protein expression><recombinant virus><resistant><response><restenosis><self assembly><short interfering RNA delivery><siRNA><siRNA delivery><small interfering RNA delivery><thrombotic disease><thrombotic disorder><tool><translational opportunities><translational potential><treatment strategy><uptake><vascular><vascular smooth muscle cell proliferation><vulnerable plaque>