# Selective Uptake and Hydrolysis of Cholesteryl Ester by SR-BI

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $385,000

## Abstract

PROJECT SUMMARY
The receptor-ligand complex of scavenger receptor class B type I (SR-BI) and HDL is responsible for cholesterol
disposal from the body via reverse cholesterol transport (RCT) and is critical in the prevention of atherosclerosis.
The long-term objective of our research is to understand the mechanisms that regulate SR-BI-mediated
delivery of cholesteryl ester (CE) from HDL to the liver for excretion. The scientific premise of this application
is based on a growing body of literature that suggests CVD risk can be reduced by strategies that promote
cholesterol clearance through enhanced cholesterol efflux and RCT. The premise is also supported by mutations
in SCARB1 (the human SR-BI gene), identified in patients with high HDL-C, that prevent the selective uptake of
HDL-CE and increase the risk of CVD. While efficient clearance of HDL-C hinges on the last steps of RCT,
studies on the importance of the SR-BI/HDL interaction that triggers selective uptake of HDL-CE remain limited.
In the previous funding cycle, our biggest discovery was the first high-resolution NMR structure of a region of
SR-BI that encompasses the C-terminal transmembrane (TM) domain and contributes to SR-BI oligomerization,
in addition to an adjacent extracellular region that harbors a short alpha helix with unique hydrophobic properties.
In this application, we build on these exciting novel findings and additional promising preliminary data to test the
overall hypothesis that cholesterol flux via RCT is driven by structural features of SR-BI that are important for
membrane association and receptor oligomerization. In Aim 1, we will use structure-guided mutagenesis and a
series of innovative biophysical techniques to determine whether receptor/membrane interactions involving a
putative extracellular juxtamembrane helix are required to mediate the cholesterol transport functions of SR-BI.
Next, we will test the in vivo importance of the juxtamembrane helix by assessing macrophage-to-feces RCT in mice
expressing mutant SR-BI receptors where helix hydrophobicity has been altered. In Aim 2, we will use cutting-edge
NMR strategies and paramagnetic relaxation experiments, as well as structure-guided mutagenesis, to identify
the organization of the SR-BI oligomer, a complex deemed essential for the movement of cholesterol from HDL
to cells. Further, we will map the precise binding interfaces between TM domains of SR-BI that are likely critical
in mediating the selective uptake of HDL-CE into the plasma membrane. Finally, in Aim 3, using a non-
oligomerizing mutant of SR-BI and relevant controls, we will perform macrophage-to-feces RCT studies, as well
as atherosclerosis studies, to define the in vivo functional relevance of SR-BI oligomerization in murine models.
The combined use in vitro and in vivo studies, together with innovative and state-of-the-art technologies, will
advance our knowledge of the molecular architecture of SR-BI. Importantly, the outcomes of our studies...

## Key facts

- **NIH application ID:** 10375464
- **Project number:** 5R01HL058012-25
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Daisy Sahoo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 1997-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375464

## Citation

> US National Institutes of Health, RePORTER application 10375464, Selective Uptake and Hydrolysis of Cholesteryl Ester by SR-BI (5R01HL058012-25). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10375464. Licensed CC0.

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