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Principal Investigator: Olga Gursky
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2024
Award: $445,637
Funding agency: National Institute of General Medical Sciences
Abstract
Aberrant lipoprotein metabolism is a hallmark of obesity that affects >40% of Americans. Obesity and its com-
plications, including type-2 diabetes (T2D), cardiovascular, amyloid and severe viral diseases, are the leading
causes of premature death. The ultimate goal of this research is to help diagnose and treat these disorders. This
project addresses critical unresolved questions in the lipoprotein functionality in obesity. High-, low- and very low-
density lipoproteins (HDL, LDL and VLDL) are diverse nanoparticles comprised of lipids and apolipoproteins that
direct lipid metabolism in plasma. This process is extremely complex and many details are unknown. Our current
focus is on the interactions of lipoproteins and proteins with heparan sulfate (HS), which can trigger both cardio-
vascular and amyloid diseases. We will determine the molecular mechanisms of apolipoprotein-HS interactions
and altered lipoprotein functionality in obesity. Our powerful approach, which integrates a wide array of biochem-
ical, biophysical and computational tools, enabled us to postulate compelling new hypotheses that will be tested
in three complementary specific aims. Aim 1 will determine how lipoprotein functionality changes in obesity be-
fore and after treatment. Lipoproteins from healthy and morbidly obese subjects will be isolated based on the
heparin binding affinity, and their biochemical and functional properties will be determined. Our new hypothesis
supported by strong pilot studies will be tested: small particles formed upon action of lipoprotein lipase on circu-
lating VLDL provide novel biomarkers of obesity and readouts for treatment. Aim 2 will define the biochemical
and functional details of serum amyloid A (SAA) transfer from HDL to LDL in obesity. Our pilot studies indicate
that transfer of this small protein induces pro-atherogenic changes in LDL, and suggest two hypotheses that will
be tested: i) new mechanistic links between obesity, elevated SAA and atherosclerosis, and ii) novel beneficial
role of SAA as a lipid scavenger in obesity. Aim 3 will determine how HS and heparin affect SAA misfolding in
amyloid A (AA) amyloidosis, a life-threatening complication of obesity and chronic inflammation. SAA binding to
HS is a therapeutic target in AA amyloidosis but molecular details are lacking. Our pilot studies suggest that: i)
SAA binding to HS initiates an extracellular pathway of amyloid deposition; ii) periodic anionic arrays in HS bind
to stacks of basic residues in amyloid and stabilize amyloid nuclei. To test these intriguing new ideas, we will
combine biochemical, biophysical, hydrogen-deuterium exchange mass spectrometry, and computational meth-
ods with atomic structures of SAA in crystals and fibrils. Outcome: this research will identify new mechanistic
links between obesity and atherosclerosis; verify the hypothetical vital role of SAA as a lipid scavenger; clarify
its misfolding pathway in amyloid; and help develop new diagnostic tools and treatments for obesity and related
disorders. Broader impact of this research is that it will: i) help understand and modulate the causal link between
obesity, T2D and severe COVID-19 disease, and ii) uncover the molecular underpinnings of HS-amyloid inter-
actions that can critically impact not only in AA but also Alzheimer's and other major amyloid diseases.
Terms: <AD dementia><APOA2><ARGII protein><Acceleration><Address><Adult-Onset Diabetes Mellitus><Affect><Affinity><Affinity Chromatography><After Care><After-Treatment><Aftercare><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><American><Amyloid><Amyloid A Precursor><Amyloid A Protein-Related Serum Component><Amyloid Protein AA Precursor><Amyloid Protein SAA><Amyloid Serum Protein SAA><Amyloid Substance><Amyloid deposition><Amyloid-Related Serum Protein (SAA)><Amyloidosis><Apo A-1><Apo A-2><Apo A-I><Apo A-II><Apo A1><Apo A2><Apo AI><Apo AII><Apo-B><Apo-E><ApoA-1><ApoA-2><ApoA-I><ApoA-II><ApoB><ApoE><ApoE protein><Apolipoprotein A-1><Apolipoprotein A-2><Apolipoprotein A-I><Apolipoprotein A-II><Apolipoprotein A1><Apolipoprotein A2><Apolipoprotein AI><Apolipoprotein AII><Apolipoprotein E><Apolipoproteins><Apolipoproteins B><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Binding><Biochemical><Biologic Models><Biological Markers><Biological Models><Biophysics><Blood Plasma><Books><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 fatality><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 mortality><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 mortality><COVID19 related death><COVID19 related fatality><COVID19 related mortality><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cartoons><Cell Body><Cell Nucleus><Cells><Cessation of life><Cholesterol><Chronic><Complex><Complication><Computational toolkit><Computing Methodologies><DAG lipase><Data Set><Death><Deposit><Deposition><Deuterium><Diacylglycerol Lipase><Diagnosis><Diglyceride Lipase><Disease><Disease Management><Disorder><Disorder Management><Goals><H element><H2 isotope><HDL><HDL Lipoproteins><Heart Vascular><Heavy Lipoproteins><Heparan Sulfate><Heparin><Heparin Binding><Heparin-Clearing Factor><Heparinic Acid><Heparitin Sulfate><High Density Lipoproteins><High density lipoprotein><Human><Hydrogen><In Vitro><Inflammation><Intermediary Metabolism><Ketosis-Resistant Diabetes Mellitus><Kinetics><LDL><LDL Lipoproteins><Life><Link><Lipemia-Clearing Factor><Lipids><Lipolysis><Lipoprotein (a)><Lipoprotein Lp(a)><Lipoproteins><Low-Density Lipoproteins><Lp(a)><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Maturity-Onset Diabetes Mellitus><Measures><Metabolic><Metabolic Processes><Metabolism><Minor><Model System><Modeling><Modern Man><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Morbid Obesity><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nucleus><Obesity><Outcome><Particle Size><Pathway interactions><Patients><Periodicals><Peripheral><Pilot Projects><Plasma><Plasma Serum><Population><Post-Heparin Lipase><Postheparin Lipase><Postheparin Lipoprotein Lipase><Prebeta-Lipoproteins><Primary Senile Degenerative Dementia><Process><Progress Reports><Property><Proteins><Public Health><Publications><Receptor Cell><Research><Reticuloendothelial System, Serum, Plasma><Role><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 mortality><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><Scientific Publication><Serum A Related Protein><Serum Amyloid A><Serum amyloid A protein><Severe obesity><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Structure><Surface><T2 DM><T2D><T2DM><Testing><Triacylglycero-protein acylhydrolase><Triacylglycerol><Triglycerides><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><VLDL><VLDL Lipoproteins><Very low density lipoprotein><Viral Diseases><Virus Diseases><Work><aberrant protein folding><abnormal protein folding><adiposity><adult onset diabetes><affinity purification><alpha-Lipoproteins><amyloid assembly><amyloid disease><amyloid formation><apo(a)II protein><apolipoprotein(a)-related protein II><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><bariatric surgery><beta-Lipoproteins><bio-markers><biochemical tools><biochemistry tools><biologic marker><biomarker><biophysical equipment><biophysical foundation><biophysical principles><biophysical sciences><biophysical tools><cardiovascular disorder><circulatory system><clearing factor lipase><computational methodology><computational methods><computational toolbox><computational tools><computational toolset><computer based method><computer methods><computerized tools><computing method><conformation><conformational><conformational state><conformationally><conformations><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 mortality><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease-19 mortality><corpulence><crosslink><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><diagnostic tool><disease risk><disorder risk><extracellular><extreme obesity><fat metabolism><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><fundamental research><gastric banding><gastric bypass surgery><heparin bound><implantable gastric stimulation banding><in vivo><ketosis resistant diabetes><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lipid metabolism><lipoprotein lipase><lipoprotein triglyceride><maturity onset diabetes><mimetics><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><nano particle><nano-sized particle><nanoparticle><nanosized particle><new diagnostics><new marker><next generation diagnostics><novel><novel biomarker><novel diagnostics><novel marker><obese individuals><obese patients><obese people><obese person><obese population><obese subjects><obesity biomarkers><obesity intervention><obesity surgery><obesity therapy><obesity treatment><obesity-related biomarkers><particle><pathologic protein folding><pathway><patients with obesity><periodic><periodical><pilot study><post treatment><premature><prematurity><primary degenerative dementia><protein misfolding><senile dementia of the Alzheimer type><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><stem><stomach stapling><therapeutic target><tissue tropism><triacylglycerol protein acylhydrolase><type 2 DM><type II DM><type two diabetes><viral infection><virus infection><virus-induced disease><weight loss surgery>