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Principal Investigator: SonBinh TheBao Nguyen
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2019
Award: $237,000
Funding agency: National Institute on Aging
PROJECT SUMMARY
Cholesterol has been linked to several cardiac and brain vascular diseases, dementias, diabetes, and cancer.
Emerging data suggests that such diseases can be traced back to an imbalance in cholesterol transport
mediated by high-density lipoproteins (HDLs), specifically attributed to reduced amount and function of native
HDLs. As such, synthetic HDL nanoparticles (HDL NPs) have been proposed as next-generation therapeutics
for treating these diseases. However, because the development of materials has lagged far behind the pace of
biological discovery and understanding, costly failures in the clinic have resulted, reinforcing the desperate
need for new approaches to HDL-inspired therapies. To be successful, synthetic HDL NPs must accurately
mimic native HDLs in size, shape, cholesterol-uptake capacity, and functional capacity required to manipulate
and transport cellular cholesterol in an effective manner. To this end, we are seeking to develop, for the first
time, a synthetic strategy to tune HDL NPs so that their form and function can be exquisitely and optimally
manipulated around a set of parameters defined by native HDLs. To that end, we have constructed a bio-
inspired HDL NP mimetic by assembling the HDL-defining apolipoprotein A-I (apo A-I) and phospholipids
around multifunctional organic core (MOC) templates. This approach appears to be highly promising, as these
organic HDL NPs (OHDL NPs) closely mimic natural HDLs in their size (~10 nm) and ability to efflux
cholesterol from lipid-laden macrophages. Here we propose to optimize the synthesis and purification of OHDL
NPs, through modulation of the MOC and downstream synthetic steps, characterize the OHDL NPs, quantify
the ability of OHDL NPs to efflux and influx cholesterol and reduce inflammation in vitro, and reduce
atherosclerotic plaque burden in a mouse model of atherosclerosis. Through these studies we will generate an
optimal OHDL NP therapeutic for the modulation of cholesterol flux, and demonstrate both in vitro and in vivo
the efficacy of OHDL NPs at reducing inflammation and atherosclerotic plaque formation.
Terms: <Abscission><Activities of Daily Living><Activities of everyday life><Acute><Address><Age><Amentia><Amides><Animal Model><Animal Models and Related Studies><Anti-inflammatory><Antiinflammatory Effect><Apo A-1><Apo A-I><Apo A1><Apo AI><ApoA-1><ApoA-I><Apolipoprotein A-1><Apolipoprotein A-I><Apolipoprotein A1><Apolipoprotein AI><Area><Arterial Fatty Streak><Arterial Fatty Streaks><Arteries><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Back><Binding><Biological><Brain Vascular Disorders><Caliber><Cancers><Cardiac><Cause of Death><Cell Body><Cells><Cerebrovascular Disease><Cerebrovascular Disorders><Chemistry><Cholesterol><Cholesterol Esters><Cholesteryl Esters><Choline Glycerophospholipids><Choline Phosphoglycerides><Chronic><Clinic><Complex><Critical Paths><Critical Pathways><DNA><Data><Dementia><Deoxyribonucleic Acid><Deposit><Deposition><Development><Diabetes Mellitus><Diameter><Disease><Disorder><Dorsum><Drugs><Excision><Extirpation><Failure><Generations><Goals><Gold><HDL><HDL Lipoproteins><HDL therapy><Half-Life><Heavy Lipoproteins><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><High Density Lipoprotein therapy><High Density Lipoproteins><High density lipoprotein><In Vitro><Inflammation><Intervention><Intervention Strategies><Intracranial Vascular Diseases><Intracranial Vascular Disorders><LDL><LDL Cholesterol><LDL Cholesterol Lipoproteins><LDL Lipoproteins><Lead><Lecithin><Length><Link><Lipid-Laden Macrophage><Lipids><Liver Cells><Low Density Lipoprotein Cholesterol><Low-Density Lipoproteins><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Medical><Medication><Molecular Interaction><Myelogenous><Myeloid><Oligo><Oligonucleotides><Pathway interactions><Patients><Pb element><Pharmaceutic Preparations><Pharmaceutical Preparations><Phosphatides><Phosphatidylcholines><Phospholipids><Process><Property><Proteins><Receptor Protein><Recombinants><Removal><Renal clearance function><Residual><Residual state><Safety><Saline><Saline Solution><Shapes><Solid><Structure><Surface><Surgical Removal><Therapeutic><Time><Transferase><Transferase Gene><Translations><Treatment Efficacy><Trees><Vascular Diseases><Vascular Disorder><aged population><ages><aging population><alpha-Lipoproteins><analog><anti-inflammatory effect><antiinflammatory><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><beta-Lipoprotein Cholesterol><beta-Lipoproteins><biocompatibility><biomaterial compatibility><blood vessel disorder><brain vascular disease><brain vascular dysfunction><burden of disease><burden of illness><cardiovascular disease risk><cardiovascular disorder risk><cerebral vascular disease><cerebral vascular dysfunction><cerebrovascular dysfunction><cost><daily living functionality><developmental><diabetes><disease burden><drug/agent><experiment><experimental research><experimental study><flexibility><flexible><functional ability><functional capacity><gold nano particle><gold nanoparticle><heavy metal Pb><heavy metal lead><in vivo><intervention efficacy><interventional strategy><intracranial vascular dysfunction><macrophage><malignancy><mimetics><model of animal><model organism><mouse model><murine model><nano gold><nano particle><nano-sized particle><nanoGold><nanoparticle><nanosized particle><neoplasm/cancer><new approaches><new drug treatments><new drugs><new therapeutics><new therapy><next generation><next generation therapeutics><novel approaches><novel drug treatments><novel drugs><novel strategies><novel strategy><novel therapeutics><novel therapy><oligos><particle><pathway><population aging><receptor><renal clearance><resection><scaffold><scaffolding><sound><stem><success><therapeutic efficacy><therapeutic nanoparticles><therapeutically effective><therapy efficacy><uptake><vascular dysfunction><vasculopathy><vulnerable plaque><years of life lost to disability><years of life lost to disease>