# Apolipoprotein conformation in amyloid and cardiovascular diseases

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $427,652

## Abstract

PROJECT SUMMARY / ABSTRACT
The overall goal of this grant has been to understand in molecular details the action of apolipoproteins (apos)
and lipoproteins in health and disease. The current focus is on human apoA-I, the major protein of plasma
high-density lipoproteins (HDL, a.k.a. good cholesterol) that remove cholesterol from cells and protect against
cardiovascular disease. ApoA-I can be released from HDL in a labile lipid-poor/free state that is the precursor of
amyloid, and can cause two forms of systemic human amyloidosis. In the acquired form, apoA-I deposits in the
arteries as fibrils, which augments atherosclerosis. In the hereditary form, fragments of mutant apoA-I deposit
in vital organs (kidney, liver, nerves, etc.) and damage them. There is no cure for this life-threatening disease
and the only current treatment is organ transplant. To pinpoint therapeutic targets, we must understand what
determines the dynamic equilibrium between the generation of the amyloid precursor, its clearance, and its
misfolding, from the native helix-bundle structure in free apoA-I to the insoluble cross-β-sheet in amyloid.
Unraveling the complex process of protein misfolding and proteostasis to block systemic amyloidosis has been
very challenging but not impossible. To this end we have integrated high- and low-resolution structural and
spectroscopic methods (circular dichroism, fluorescence, hydrogen-deuterium exchange, etc.) with biochemical
and computational tools. Analysis of several disease-causing mutants enabled us to propose the first molecular
mechanism of apoA-I misfolding. We postulated that perturbed packing in amyloid `hot spots' combined with the
structural integrity of the native fold make the protein amyloidogenic. This idea can be extended to other 
proteins; it helps explain why structural destabilization of many globular proteins is neither necessary nor sufficient
to cause amyloid disease. These and other new ideas will be rigorously tested in the next cycle of this grant.
Aim 1 will elucidate the molecular mechanism of apoA-I misfolding in hereditary amyloidosis. We will determine
how the disease-causing mutations perturb the native protein conformation in sensitive segments to promote
β-aggregation vs. proteolysis. Cell-based studies will unveil why mutation carriers are at a low risk of
atherosclerosis despite low levels of plasma HDL. Aim 2 will identify the similarities and differences in the
molecular basis for hereditary and acquired amyloidoses, and will establish the structure-toxicity relationship in
aggregated forms of apoA-I. Aim 3 will define the role of lipids in apoA-I misfolding. This aim will test our
hypothesis that lipid-lowering approaches hold therapeutic potential for apoA-I amyloidoses.
This research opens a new frontier that goes beyond protein stability to identify key drivers of protein misfolding
in vivo. The results will unveil the link between amyloidogenic and cardioprotective properties of apoA-I, help
fin...

## Key facts

- **NIH application ID:** 9999601
- **Project number:** 5R01GM067260-18
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Olga Gursky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $427,652
- **Award type:** 5
- **Project period:** 1998-12-15 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999601

## Citation

> US National Institutes of Health, RePORTER application 9999601, Apolipoprotein conformation in amyloid and cardiovascular diseases (5R01GM067260-18). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999601. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*