# Multi-disciplinary Approaches to HDL Structure, Assembly, and Functional Heterogeneity

> **NIH NIH P01** · UNIVERSITY OF CINCINNATI · 2024 · $2,494,366

## Abstract

SUMMARY (Entire PPG)
 The development of new cardioprotective drugs and accurate metrics for cardiovascular risk is being
hindered, we believe, by the failure to correctly identify the cardioprotective forms of high-density lipoprotein
(HDL) and inadequate knowledge about the mechanisms that remove cholesterol from the artery wall. This
renewal application will address these issues by continuing dynamic interactions among seven world-class
scientists who study HDL from diverse, but complementary, viewpoints. HDL, an important mediator of
cholesterol transport, is created when its most abundant scaffold protein, apolipoprotein A-I (APOA1), interacts
with ATP-binding cassette transporter A1 (ABCA1). This process is critical for removing cholesterol from
macrophages. Indeed, the capacity for human plasma HDL to promote cholesterol efflux (CEC) is more
diagnostic for cardiovascular disease (CVD) risk than the traditional measure of HDL’s cholesterol content. The
central hypothesis of this multidisciplinary Program Project Grant is that ABCA1 engages in highly specific
interactions with APOA1 particles that may or may not contain lipid to produce cardioprotective HDL. Our
objective is to derive a molecular understanding of this pathway and the roles played by HDL subspecies in
the setting of diabetes. We will use three general overlapping approaches: 1) calibrated ion mobility
spectrometry to relate the size and number of specific HDL particles to CEC and CVD risk in diabetic patients,
2) detailed in vitro mechanistic approaches to unravel the factors that allow specific lipidated HDL particles to
interact with ABCA1, and 3) cryo-EM and computational studies of the structure and mechanism of ABCA1’s
action. Our plan focuses on three Projects at four sites: Project 1: Cardioprotection by extra-small HDL
particles – Jay Heinecke, Project Leader; Karin Bornfeldt, Co-I (University of Washington); Project 2:
Mechanism of ABCA1-mediated cholesterol efflux to lipidated HDL – W. Sean Davidson, Project Leader
and PPG Principal Investigator (University of Cincinnati); Project 3: Mechanisms of
phospholipid/cholesterol translocation by ABCA1 – Jere Segrest, Project Leader (Vanderbilt University);
Steve Aller, Co-I (University of Alabama at Birmingham). Additionally, four core facilities will drive scientific
synergy and cost-effective use of NIH resources: Core A: Administration – W. Sean Davidson, Core Leader,
will provide administrative support for the Program. Core B: Computational Biology – Jere Segrest, Core
Leader, will perform molecular modeling, homology modeling, and double/single state normal mode analyses
for structural studies. Core C: Lipoprotein Quantitation and Function – Tomas Vaisar, Core Leader;
Chongren Tang, Co-I, will quantify i) HDL particle number (the sizes and concentrations of HDL particles) and
ii) the cholesterol efflux capacity of various HDLs and ABCA1 mutants. Core D: Apo/Lipoprotein Production
– W. Sean Davidson, Core Leader, will ...

## Key facts

- **NIH application ID:** 10903851
- **Project number:** 5P01HL128203-07
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** W Sean Davidson
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,494,366
- **Award type:** 5
- **Project period:** 2016-09-15 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903851

## Citation

> US National Institutes of Health, RePORTER application 10903851, Multi-disciplinary Approaches to HDL Structure, Assembly, and Functional Heterogeneity (5P01HL128203-07). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10903851. Licensed CC0.

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