Document text
Principal Investigator: Olga Gursky
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2023
Award: $52,010
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><Address><Adult-Onset Diabetes Mellitus><Affect><Affinity><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><Apolipoproteins><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Binding><Biochemical><Biophysics><Blood Plasma><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell Nucleus><Cessation of life><Cholesterol><Chronic><Complex><Complication><Computing Methodologies><DAG lipase><Death><Deuterium><Diacylglycerol Lipase><Diagnosis><Diglyceride Lipase><Disease><Disorder><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><Hydrogen><Inflammation><Intermediary Metabolism><Ketosis-Resistant Diabetes Mellitus><LDL><LDL Lipoproteins><Life><Link><Lipemia-Clearing Factor><Lipids><Lipoproteins><Low-Density Lipoproteins><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Maturity-Onset Diabetes Mellitus><Metabolic Processes><Metabolism><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><Pathway interactions><Periodicals><Pilot Projects><Plasma><Plasma Serum><Post-Heparin Lipase><Postheparin Lipase><Postheparin Lipoprotein Lipase><Prebeta-Lipoproteins><Primary Senile Degenerative Dementia><Process><Property><Proteins><Public Health><Research><Reticuloendothelial System, Serum, Plasma><Role><Serum A Related Protein><Serum Amyloid A><Serum amyloid A protein><Severe obesity><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Structure><T2 DM><T2D><T2DM><Testing><Triacylglycero-protein acylhydrolase><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><adiposity><adult onset diabetes><alpha-Lipoproteins><amyloid disease><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><beta-Lipoproteins><biochemical tools><biochemistry tools><biophysical equipment><biophysical foundation><biophysical principles><biophysical sciences><biophysical tools><cardiovascular disorder><circulatory system><clearing factor lipase><computational methodology><computational methods><computational tools><computer based method><computer methods><computerized tools><computing method><conformation><conformational><conformational state><conformationally><conformations><corpulence><diagnostic tool><extracellular><extreme obesity><fat metabolism><fundamental research><heparin bound><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><maturity onset diabetes><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 people><obese person><obese population><obese subjects><obesity biomarkers><obesity intervention><obesity therapy><obesity treatment><obesity-related biomarkers><particle><pathway><periodic><periodical><pilot study><post treatment><premature><prematurity><primary degenerative dementia><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 coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><therapeutic target><triacylglycerol protein acylhydrolase><type 2 DM><type II DM><type two diabetes><viral infection><virus infection><virus-induced disease>