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Principal Investigator: Olga Gursky
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2024
Award: $296,685
Funding agency: National Institute of General Medical Sciences
Amyloid diseases afflict 10 million patients worldwide. This project is focused on AA amyloidosis, a life-threatening complication of chronic inflammation wherein deposition of serum amyloid A (SAA), and its fragments causes kidney and liver damage and, if untreated, death. There is no cure for AA and the treatment options are very limited. To help design amyloid-specific therapies, we will determine how lipids and GAGs, the major ligands of SAA, influence its misfolding. Our prior research revealed that SAA clears diverse lipids from the sites of injury by sequestering them into nanoparticles that facilitate sPLA2 lipolysis; we established the structural basis for this SAA action. Our goal now is to determine how this lipid-scavenging function is linked to pathologic amyloid deposition. Our hypothesis rooted in extensive pilot studies is that lipoprotein formation by SAA is antagonistic to amyloid formation while GAG binding is agonistic. Our powerful approach integrates an array of biochemical, biophysical and computational methods to test this and other new ideas in 3 complementary Specific Aims. Aim 1 will determine how biochemical composition of SAA-lipid complexes influences amyloid formation. Murine or human recombinant SAA will be reconstituted with diverse lipids in complexes that will be selectively hydrolyzed, and amyloid formation will be explored by spectroscopic, electron microscopic, immunochemical and other tools. The results will help identify key steps in SAA-lipid homeostasis that critically influence amyloid formation, and will test a fascinating idea: lipid-modifying strategies may help treat AA amyloidosis. Aim 2 will dissect the amyloidogenic pathways of lipid-bound and free SAA and how GAGs affect these pathways. We will explore the interplay between SAA binding to lipids and GAGs, lipolysis, and formation of amyloid oligomers and fibrils. The results will help target SAA-GAG interactions in AA and other amyloid diseases. Aim 3 will utilize our new versatile ELISA-based assay that uses micrograms of protein to quantify the binding to amyloid modulators during fibrillogenesis. SAA binding to various GAG mimetics and small-molecule drugs will be used as a model; key results will be validated by other methods. Our pilot studies explain the failure of prior clinical trials for AA and suggest that larger molecules can block the SAA-GAG binding. Moreover, we will use our new assay to determine how other amyloid proteins (A, -synuclein, tau, TTR, etc.) interact with diverse amyloid modulators (GAGs, apoE, etc.) Impact: this project will advance AA research and therapeutic targeting to a new level. Moreover, it will develop new tools and concepts that can be extrapolated to other systemic and neurodegenerative amyloid diseases, such as Alzheimer’s and other major diseases.
Terms: <AD dementia><Abscission><Acute><Acute-Phase Proteins><Acute-Phase Reactants><Address><Affect><Affinity Chromatography><All-Trans-Retinol><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Amyloid><Amyloid A Precursor><Amyloid A Protein-Related Serum Component><Amyloid A4 Protein Precursor><Amyloid Protein AA Precursor><Amyloid Protein Precursor><Amyloid Protein SAA><Amyloid Proteins><Amyloid Serum Protein SAA><Amyloid Substance><Amyloid beta-Protein Precursor><Amyloid deposition><Amyloid β-Protein Precursor><Amyloid-Related Serum Protein (SAA)><Amyloidosis><Anisotropy><Anti-Infective vitamin><Antibodies><Antixerophthalmic vitamin><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Assay><Atrophic Arthritis><Autoimmune Diseases><Autoregulation><Axerophthol><Axerophtholum><Binding><Bioassay><Biochemical><Biological Assay><Biosterol><Blood Plasma><Body Tissues><Cancers><Cell membrane><Cessation of life><Chronic><Circular Dichroism><Clear Cell><Clinical Trials><Complex><Complication><Computing Methodologies><Crohn disease><Crohn's><Crohn's disease><Crohn's disorder><Cytoplasmic Membrane><Data><Death><Deposit><Deposition><Development><Disease><Disorder><Dot Immunoblotting><Drops><Drugs><EC 3.1.1.4><ELISA><Electron Microscopy><Electrons><Ensure><Enzyme-Linked Immunosorbent Assay><Excision><Extirpation><FTIR><FTIR spectroscopy><Face><Failure><Fatty Acids><Fluorescence Spectroscopy><Glycosaminoglycans><Goals><Granulomatous Enteritis><HDL><HDL Lipoproteins><Health><Heavy Lipoproteins><Heparan Sulfate><Heparin><Heparinic Acid><Heparitin Sulfate><High Density Lipoproteins><High density lipoprotein><Homeostasis><Human><Hydrolysis><Hydrophobicity><Incubated><Infection><Inflammation><Injury><Injury to Liver><Lard-Factor><Lecithinase A2><Life><Ligands><Link><Lipid Binding><Lipids><Lipolysis><Lipoproteins><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MT-bound tau><MTB infection><Malignant Neoplasms><Malignant Tumor><Medication><Metabolic><Methods><Mice><Mice Mammals><Microscopic><Modeling><Modern Man><Molecular><Molecular Interaction><Molecular Sieve Chromatography><Mucopolysaccharides><Murine><Mus><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Negative Beta Particle><Negatrons><Nerve Degeneration><Neuron Degeneration><Oleovitamin A><Ophthalamin><Organ><PLA2><Paralysis Agitans><Parkinson><Parkinson Disease><Pathologic><Pathway interactions><Patients><Pharmaceutical Preparations><Phospholipase A2><Physiological Homeostasis><Pilot Projects><Plasma><Plasma Membrane><Plasma Serum><Play><Primary Parkinsonism><Primary Senile Degenerative Dementia><Process><Progress Reports><Protein Cleavage><Proteins><Proteolysis><Publications><Publishing><Recombinants><Removal><Research><Reticuloendothelial System, Serum, Plasma><Rheumatoid Arthritis><Role><Scientific Publication><Serum A Related Protein><Serum Amyloid A><Serum amyloid A protein><Site><Size Exclusion Chromatography><Spectroscopy, Fourier Transform Infrared><Structure><Surgical Removal><TB infection><Testing><Tissues><Tuberculosis><Vitamin A Alcohol><affinity purification><alpha-Lipoproteins><amyloid assembly><amyloid disease><amyloid formation><amyloid precursor protein><autoimmune condition><autoimmune disorder><autoimmunity disease><biophysical approaches><biophysical methodology><biophysical methods><biophysical techniques><chronic infection><cofactor><computational methodology><computational methods><computer based method><computer methods><computing method><damage to kidney><design><designing><developmental><disseminated TB><disseminated tuberculosis><dot blotting><drug/agent><eleocolitis><enzyme linked immunoassay><faces><facial><fascinate><feasibility research><fibrillogenesis><healing><hepatic damage><hepatic injury><infection due to Mycobacterium tuberculosis><injured><injuries><insoluble aggregate><kidney damage><lecithinase A><lipid based nanoparticle><lipid bound><lipid nanoparticle><liver damage><liver injury><malignancy><microtubule bound tau><microtubule-bound tau><mimetics><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><nano particle><nano-sized particle><nanolipoprotein particles><nanoparticle><nanosized particle><neoplasm/cancer><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal degeneration><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><particle><pathway><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><persistent infection><phosphatidase><phosphatidolipase><phosphatidylcholine 2 acylhydrolase><pilot study><plasmalemma><primary degenerative dementia><protein aggregate><protein aggregation><reconstitute><reconstitution><regional enteritis><renal damage><resection><retinol><rheumatic arthritis><senile dementia of the Alzheimer type><small molecule><social role><stem><synergism><synuclein><tau><tau Proteins><tau factor><therapeutic target><tool><tuberculosis infection><tuberculous spondyloarthropathy><τ Proteins>