# Structural basis for cardioprotective HDL

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2020 · $688,354

## Abstract

Our long-term goal is to establish the structural features responsible for the cardioprotective functions of HDL
in humans, which may have important implications for predicting CVD risk and developing HDL-targeted
therapeutics. We have recently shown that apolipoprotein A1 (APOA1), HDL’s major apolipoprotein, can
assume three different antiparallel isomeric structures we term rotamers. Strong preliminary data suggests that
the different rotamers exist in humans, and that they affect HDL size and ability to bind different proteins, and
have different abilities to promote cholesterol efflux from macrophages by the ABCA1 pathway. To determine
the physiological relevance of the APOA1 rotamers, we therefore propose two specific aims.
First, we will engineer Apoa1-/- mice to express mutated forms of human APOA1 that cause HDL to selectively
form specific rotamers of APOA1 in vivo. We will then determine the impact of the different rotamers on HDL
cholesterol efflux capacity, HDL size, HDL protein cargo, and atherosclerosis in LDL receptor-deficient mouse
models.
Second, we will complement our animal studies with analyses of HDLs of humans with and without carotid
atherosclerotic disease, and with and without diabetes. We will determine whether the distribution of specific
rotamers, HDL subspecies, and HDL protein cargo associate with cholesterol efflux capacity and whether they
associate with or predict atherosclerotic disease in these subjects. Because preliminary studies show that HDL
of diabetic patients have impaired cholesterol efflux capacity, and diabetic patients are at greatly increased risk
of cardiovascular disease, our proposed investigation of the structural features of HDL that associate with both
impaired HDL function and atherosclerotic disease could provide important insights into HDL-associated
factors that are cardioprotective but are independent of HDL cholesterol levels.

## Key facts

- **NIH application ID:** 9859254
- **Project number:** 1R01HL149685-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Karin E Bornfeldt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $688,354
- **Award type:** 1
- **Project period:** 2019-12-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859254

## Citation

> US National Institutes of Health, RePORTER application 9859254, Structural basis for cardioprotective HDL (1R01HL149685-01). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9859254. Licensed CC0.

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