Friday, April 26, 2024
4/26/2024
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
