# Structure and Function of Serum Amyloid A in Health and Disease

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2024 · $106,758

## Abstract

Abstract
Amyloid diseases afflict >10 million patients worldwide and involve pathologic deposition of ~40 human proteins
as fibrils. This project is focused on AA amyloidosis, a life-threatening complication of chronic inflammation
wherein deposition of a small plasma protein, 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 glycosaminoglycans (GAGs), the major lig-
ands 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 a wide array of biochemical,
biophysical and computational methods to test this and other new ideas in three 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 hydro-
lyzed, 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 pathway of lipid-bound and free SAA and the effects of GAGs. Our multipronged experimental-
computational approach will explore the interplay between SAA binding to lipids, to GAGs, and formation of
amyloid oligomers and fibrils. SAA-GAG interactions are a validated therapeutic target in AA, but a small-mole-
cule drug designed to block them was inefficient in clinical trials. Our hypothesis is that GAGs act as amyloid
scaffolds; to test it, we will harness cryo-EM structures of ex vivo amyloids for molecular dynamics simulations.
The results will help target SAA-GAG interactions in AA and will provide sharp insights into amyloid-GAG inter-
actions in other 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 pro...

## Key facts

- **NIH application ID:** 11014597
- **Project number:** 3R01GM135158-05S1
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Olga Gursky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $106,758
- **Award type:** 3
- **Project period:** 2020-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11014597

## Citation

> US National Institutes of Health, RePORTER application 11014597, Structure and Function of Serum Amyloid A in Health and Disease (3R01GM135158-05S1). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/11014597. Licensed CC0.

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