# TRANSFORMATIVE LIPID EXCHANGE APPROACHES TO STUDY MEMBRANE ORGANIZATION

> **NIH NIH R35** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $186,546

## Abstract

This project aims to understand biomembrane structure and function with the aid of a recent lab-achieved
breakthrough in control of membrane phospholipid and sphingolipid composition via cyclodextrin-catalyzed
lipid exchange. This permits preparation of lipid vesicles mimicking natural membranes closely in terms of both
lipid composition and, for the first time, lipid asymmetry, the difference in the lipid composition in the inner and
outer lipid layers characteristic of many natural membranes. The method is also being extended to control of
lipid composition in living cells. These methods are being applied to solve long-standing issues of membrane
domain formation. We and collaborator Dr. Deborah Brown proposed in 1994 what remains the working model
in the field: cell membrane domains form due to segregation of sphingolipid-cholesterol rich liquid ordered (Lo)
domains from unsaturated lipid rich liquid disordered domains. Although such domains are readily observed in
artificial lipid vesicles, and careful studies document their presence in living cells, domains remain controversial
and poorly characterized. This project will use lipid exchange to overcome roadblocks to progress in studies of
membrane domains. First, studies using asymmetric lipid vesicles that mimic cell membranes much more
closely than the symmetric vesicles employed in the past will define the rules governing domain properties and
formation by lipids and proteins. This includes testing the long-standing hypothesis that lipid-induced signal
transduction across membranes can result from coupling between physical properties of lipids in the inner and
outer lipid layers of a membrane. Knowledge gained from these studies will reveal how to manipulate lipids and
proteins in cells to control domain formation and protein association with domains, and thus how to explore
their function. Second, domains will be studied with more tractable living systems and methods. We found that
the cholesterol-containing bacterium Borrelia burgdorferi, the causative agent of Lyme disease, has domain
size sufficient for visualization by electron microscopy and facile fluorescence domain detection using FRET,
plus accessibility to altering sterol chemical structure to allow controlled modulation of domain formation. This
made it possible to unequivocally identify bacterial Lo domains in vitro and in vivo. Studies will be extended to
other pathogenic bacteria likely to contain Lo domains: Helicobacter pylori, the cause of ulcers and some
cancers, and S. aureus, drug-resistant strains of which (MRSA) are a major public health threat. Studies will
define the properties of bacterial domains, the principles behind their formation, and potential biomedical
implications. Studies will then be extended to mammalian cells taking advantage of our discovery of a
cyclodextrin that can fully exchange plasma membranes outer leaflet lipids with exogenous phospholipid and
sphingolipid without disturbing cell sterols. Us...

## Key facts

- **NIH application ID:** 10114663
- **Project number:** 3R35GM122493-04S1
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Erwin London
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $186,546
- **Award type:** 3
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114663

## Citation

> US National Institutes of Health, RePORTER application 10114663, TRANSFORMATIVE LIPID EXCHANGE APPROACHES TO STUDY MEMBRANE ORGANIZATION (3R35GM122493-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10114663. Licensed CC0.

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