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

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $313,500

## Abstract

Abstract
This research is focused on normal and pathologic actions of serum amyloid A (SAA), an enigmatic biomarker of
inflammation and a protein precursor of AA amyloidosis, a life-threatening complication of chronic inflammation.
SAA is a small soluble intrinsically disordered protein that increases rapidly and dramatically up to 1,000-fold in
plasma following inflammation, infection or injury. The advantage for survival of this steep but transient increase
is unclear, and the beneficial role of SAA in immune response is obscure. However, evolutionarily conserved
aspects of the SAA structure, its lipophilic character, and the rapid and major commitment of liver and local tissues
to SAA biosynthesis strongly support the importance of SAA-lipid interactions. Our new structural model suggests
how SAA binds lipids and cell receptors, thereby rerouting lipid metabolism. Pilot biochemical studies compel us
to propose a vital new role for SAA in clearing cellular membrane debris from the injured sites. Our powerful
biophysical and biochemical approach will determine the mechanism via which SAA sequesters phospholipids
and other lipids from cell membranes to facilitate their breakdown and safe removal from the injured sites in a
process that is prerequisite for tissue healing. We will also determine how various lipids and other factors
modulate amyloid formation by SAA, and thereby help decelerate or block this pathogenic process.
Three complementary specific aims develop new concepts fundamental to SAA action in immune response and
amyloid formation. Aim 1 will use an array of biophysical, structural and cell-based methods to establish
molecular underpinnings for SAA interactions with its functional ligands, lipids and CD36 cell receptor. We will
test our new structural model suggesting that SAA binds lipids via a unique apolar face whose shape defines
protein's preference for binding to highly curved lipoproteins or forming them de novo to sequester lipids. We will
determine the SAA conformation on the lipid and quantify its binding to CD36. Aim 2 will probe a novel synergy
between SAA and secretory phospholipase A2 (sPLA2), an acute-phase plasma protein upregulated
simultaneously with SAA in inflammation. Pilot studies compel us to propose a novel beneficial function of SAA
in solubilizing phospholipids and their hydrolytic products to generate substrates for sPLA2 and to remove its
products. The results will establish the hitherto unknown vital primordial role of SAA. Aim 3 will determine effects
of various lipids, their degradation products, pH and heparin sulfate on SAA amyloid formation. We will also test
our new idea that plasma lipids such as triacylglycerol modulate the SAA release from its major plasma carrier,
high-density lipoprotein, and ultimately form amyloid. The results will help determine whether lipid-lowering
therapies hold promise for treating AA amyloidosis. Completion of this research will establish raison d'etre for
this enigma...

## Key facts

- **NIH application ID:** 10321653
- **Project number:** 5R01GM135158-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Olga Gursky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $313,500
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10321653

## Citation

> US National Institutes of Health, RePORTER application 10321653, Structure and Function of Serum Amyloid A in Health and Disease (5R01GM135158-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10321653. Licensed CC0.

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