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Principal Investigator: Gary Liu
Organization: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Fiscal Year: 2021
Award: $66,390
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY/ABSTRACT
Vascular injury and disease during diabetes lead to end-organ dysfunction (kidney failure, blindness,
amputation) and cardiovascular disease that profoundly reduces patient quality of life and life expectancy. The
proposed work seeks to develop new therapeutics to prevent and arrest diabetic vascular disease, by
engineering nanoparticles to enable efficient delivery of a protein therapeutic. A major cause of vascular injury
is protein glycation, the covalent attachment of glucose to proteins that leads to advanced glycation end-
products and protein inactivation. In particular, the protein CD59, the key regulator of the membrane attack
complex (MAC), is ubiquitously expressed, and human CD59 is uniquely susceptible to glycation-inactivation
during diabetes. Human and experimental studies underscore the connection between CD59 glycation-
inactivation, complement dysregulation, and MAC deposition in tissues. Therefore, delivery of exogenous,
glycation-resistant CD59 could rescue complement regulation and mitigate complement-mediated vascular
injury in diabetes, but is challenging due to rapid clearance and non-specific serum-binding of this protein.
Moreover, a delivery strategy would need to achieve broad cell tropism (red blood cells, endothelial and
epithelial cells) and high delivery efficiency. The goal of this work is to engineer nanoparticles (NPs) to enable
efficient intravenous delivery of mouse CD59 in vivo using lipid-based NPs to improve protein
pharmacokinetics. We hypothesize that nanoparticle delivery of CD59 will mitigate cardiovascular disease and
endothelial dysfunction in diabetic mice with CD59 deficiency. In Aim 1, NPs will be optimized for
biocompatibility, protein loading, minimal non-specific uptake, and delivery in vitro. Optimized NPs will then be
evaluated in Aim 2 for biodistribution and therapeutic efficacy in preventing atherosclerosis, endothelial
dysfunction, and tissue complement deposition in diabetic, CD59-deficient animals. Successful completion of
this work could validate CD59 delivery as a clinical strategy to halt and prevent diabetic vascular complications.
The applicant, Gary Liu, aims to lead a lab as a principal investigator. One of his future research aims is to
develop new therapies for diabetic microvascular complications. This postdoctoral fellowship includes (1)
didactic training in diabetes, its complications, endocrinology, and bioinformatics; (2) scientific training in
diabetic animal models and methods for quantifying cardiovascular disease and endothelial dysfunction, and
(3) professional development and training in the responsible conduct of research in preparation for a career as
a principal investigator. Training will occur at the Koch Institute of MIT in Dr. Robert Langer’s lab, which will
provide the materials, equipment, and intellectual expertise necessary to carry out the proposed work.
Terms: <Address><Advanced Glycation End Products><Advanced Glycosylation End Products><Amputation><Animal Model><Animal Models and Related Studies><Animals><Apo-E><ApoE><Apolipoprotein E><Arterial Fatty Streak><Arterial Fatty Streaks><Artificial nano particles><Artificial nanoparticles><Assay><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Binding><Binding Proteins><Bio-Informatics><Bioassay><Bioavailability><Biodistribution><Bioinformatics><Biologic Assays><Biologic Availability><Biological Assay><Biological Availability><Blindness><Blood><Blood Circulation><Blood Reticuloendothelial System><Blood Serum><Blood Vessels><Blood erythrocyte><Blood monocyte><Bloodstream><Body Tissues><C 5b-9><C5b-9><Cardiovascular Diseases><Carrier Proteins><Cell Body><Cell Membrane Lipids><Cells><Chronic><Circulation><Clinic><Clinical><Complement><Complement Complex C5b-9><Complement Inactivators><Complement Inhibitors><Complement Membrane Attack Complex><Complement Proteins><Complications of Diabetes Mellitus><Confocal Microscopy><Cytolytic Terminal Complement Complex><D-Glucose><Deposit><Deposition><Development><Dextrose><Diabetes Complications><Diabetes Mellitus><Diabetes-Related Complications><Diabetic Angiopathies><Diabetic Complications><Diabetic Vascular Complications><Diabetic Vascular Diseases><Diabetic Vascular Disorder><Diabetic mouse><Diminished Vision><Dose><Drug Kinetics><Drugs><Dysfunction><Endocrinology><Endothelial Cells><Engineering><Epithelial Cells><Equipment><Erythrocytes><Erythrocytic><Exhibits><Fellowship><Filtration><Filtration Fractionation><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fluorescence><Frequencies><Functional disorder><Gln><Glucose><Glutamine><Goals><Half-Life><Histidine><Human><Hyperglycemia><In Vitro><Institutes><Intravenous><KO mice><Kidney><Kidney Failure><Kidney Insufficiency><Kidney Urinary System><Kinetics><Knock-out><Knock-out Mice><Knockout><Knockout Mice><L-Glutamine><L-Lysine><Label><Lead><Life Expectancy><Ligand Binding Protein><Ligand Binding Protein Gene><Lipid Bilayers><Lipids><Low Vision><Lysine><Lytotoxicity><Marrow erythrocyte><Marrow monocyte><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Medication><Membrane Attack Complex><Membrane Lipids><Metabolism and Endocrinology><Methods><Mice><Mice Mammals><Microvascular Dysfunction><Modern Man><Molecular Interaction><Molecular Weight><Murine><Mus><Mφ><Nanotechnology><Null Mouse><Organ><Partial Sight><Pathogenesis><Patients><Pb element><Phagocytes><Phagocytic Cell><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Physiologic Availability><Physiopathology><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Preparation><Principal Investigator><Property><Protein Binding><Protein Engineering><Protein Modification><Proteins><Q Levoglutamide><Q. Levoglutamide><QOL><Quality of life><Radiolabeled><Red Blood Cells><Red Cell><Reduced Vision><Regulation><Renal Failure><Renal Insufficiency><Resistance><Risk><Ristocetin Cofactor><Ristocetin-Willebrand Factor><STZ><Scintillation Counting><Serum><Serum Proteins><Streptozocin><Streptozotocin><Subnormal Vision><Surface><Terminal Complement Complex><Testing><Tissues><Training><Transport Protein Gene><Transport Proteins><Transporter Protein><Treatment Efficacy><Tropism><Vascular Diseases><Vascular Disorder><Visual impairment><Work><Zanosar><advanced glycation endproduct><advanced glycosylation endproduct><amebocyte><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><base><biocompatibility><biomaterial compatibility><blood corpuscles><blood vessel disorder><bound protein><cardiovascular disorder><cardiovascular endothelium><career><clinical translation><cross-link><crosslink><cytotoxicity><developmental><diabetes><diabetes mouse model><diabetic><drug/agent><efficacy analysis><efficacy assessment><efficacy evaluation><efficacy examination><endothelial dysfunction><engineered nano particle><engineered nanoparticle><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><flow cytophotometry><genetic protein engineering><glycation><glycemic control><heavy metal Pb><heavy metal lead><hyperglycemic><improved><in vivo><in vivo Model><injury to the vasculature><intervention efficacy><lipid bilayer membrane><lipid nanoparticle><lipophilicity><macrophage><microvascular complications><microvascular complications of diabetes><microvascular disease><model of animal><model organism><monocyte><nano particle><nano particle delivery><nano tech><nano technology><nano-sized particle><nano-technological><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><nanotech><nanotechnological><native protein drug><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><non-enzymatic glycosylation><nonenzymatic glycosylation><novel drug treatments><novel drugs><novel therapeutics><novel therapy><pathophysiology><pharmaceutical protein><prevent><preventing><protein design><protein drug agent><protein function><renal><resistant><responsible research conduct><small vessel disease><therapeutic efficacy><therapeutic protein><therapy efficacy><uptake><vascular><vascular dysfunction><vascular injury><vasculopathy><vision impairment><vision loss><visual loss><visually impaired><von Willebrand Factor><von Willebrand Protein><vulnerable plaque>