# The functional organization of mammalian membranes- Diversity Supplement

> **NIH NIH R35** · UNIVERSITY OF VIRGINIA · 2021 · $54,805

## Abstract

Project Summary
Our laboratory is focused on the functional organization of mammalian membranes to generate mechanistic
insight into the connections between lipid composition, membrane structure, and cell physiology. Membranes
host a major fraction of all cellular bioactivity, orchestrating myriad simultaneous, parallel tasks. This
functionality is enabled by the remarkable complexity and diversity of mammalian lipidomes, which give rise to
a unique combination of biophysical phenotypes, including membrane fluidity, tension, curvature, and lateral
compartmentalization. We aim for a predictive understanding of how lipidomic features determine membrane
properties, and how these in turn regulate cell functions. Progress towards this goal has been enabled by
recent methodological advances in high-throughput lipidomics, biophysical analysis of plasma membranes,
and quantitative high-resolution spectral microscopy. Using these, we have made significant advances in
understanding several interrelated aspects of lateral and transverse organization of mammalian membranes.
We have defined broad structural features responsible for protein association with ordered membrane
domains and how such domains are involved in membrane traffic. Despite these insights, there remains
remarkably little known about which proteins associate with membrane domains and why. Our experimental
and computational framework allows us to address key outstanding questions, including: what are the
structural codes for protein affinity for ordered domains, and how does protein association with membrane
domains facilitate their localization and function? In parallel, we have characterized the remarkable plasticity
of mammalian membranes (particularly their susceptibility to dietary fatty acids) and characterized the effects
of such external inputs on membrane properties and cell function. However, how cells maintain membrane
homeostasis in response to continuous challenge from dietary and other external inputs is not well
understood. Our observations suggest that interference with such homeostatic mechanisms may provide a
novel therapeutic strategy for treatment of cardiovascular disease or cancer. Finally, our most recent work has
focused on the asymmetric distribution of lipids between the two leaflets of the plasma membrane bilayer.
Although such compositional asymmetry appears to be a universal design principle for living membranes, the
selective advantages that asymmetry confers are not known. We are defining the compositional, biophysical,
and functional asymmetry of the plasma membrane in mammalian cells to answer major open questions
about the biophysical consequences of membrane asymmetry and how physical properties are coupled
across asymmetric leaflets. Functionally, intriguing recent discoveries reveal that transient loss of membrane
asymmetry is widespread during immune cell activation, and is necessary for optimal response; however, the
mechanisms underlying these effects o...

## Key facts

- **NIH application ID:** 10320538
- **Project number:** 3R35GM134949-03S1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Ilya Levental
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $54,805
- **Award type:** 3
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320538

## Citation

> US National Institutes of Health, RePORTER application 10320538, The functional organization of mammalian membranes- Diversity Supplement (3R35GM134949-03S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10320538. Licensed CC0.

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