Research Interests
Despite their ubiquity and importance, cellular membranes and their constituent lipids remain some of the most poorly understood aspects of modern cell biology. Deep, fundamental questions about their nature and functions remain unresolved:
The overall of our laboratory are to understand and manipulate the fundamental molecular mechanisms by which membrane lipids influence cellular physiology. Cellular membranes are a biophysicist’s dream: they are composites of biological macromolecules with a multitude of chemical interactions, which give rise to complex phase behaviors and physical properties. Their study inherently requires a multidisciplinary approach, which is reflected in the thoroughly interdisciplinary, collaborative constitution of our lab: an interactive team of biologists, engineers, and physicists.
- What is the purpose of the vast lipid complexity in mammalian cells?
- What is the lateral organization of membranes, how is it regulated, and how does it influence cell physiology?
- How does the cell achieve and maintain the dramatic differences in membrane composition between cellular organelles?
- How is membrane homeostasis maintained in the face of constant challenges from exogenous amphiphiles and dietary lipids?
The overall of our laboratory are to understand and manipulate the fundamental molecular mechanisms by which membrane lipids influence cellular physiology. Cellular membranes are a biophysicist’s dream: they are composites of biological macromolecules with a multitude of chemical interactions, which give rise to complex phase behaviors and physical properties. Their study inherently requires a multidisciplinary approach, which is reflected in the thoroughly interdisciplinary, collaborative constitution of our lab: an interactive team of biologists, engineers, and physicists.
How proteins get ordered - structural determinants and functional consequences of raft association
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Membrane functionality can be extended by partitioning them into lateral subdomains. One example are sphingolipid/cholesterol rich ordered domains known as lipid rafts. Although this hypothesis has been the source of much controversy, recent insights have accumulated evidence supporting their existence. However, fundamental questions remain:
To study lipid rafts in biological membranes, we use an exciting and novel tool in membrane biology, phase separation in Giant Plasma Membrane Vesicles (GPMVs). These plasma membranes, isolated directly from live cells, allow direct, rapid, and quantitative analysis of component partitioning to raft phases in eukaryotic cell membranes. Additionally, independent quantification of protein enzymatic/binding activity permits analysis of the raft-dependence of these characteristics.
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The consequences of lipidomic complexity and metabolic engineering
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Using our unique platform for plasma membrane isolation and detailed lipidomic characterization, we have discovered that mammalian membranes are remarkably complex, plastic, and diverse. We have investigated this diversity across a variety of contexts, including neuronal development, mesenchymal stem cell differentiation, and dietary fatty acid feeding.
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Life at the interface – regulation of proteins by membranes
Membrane proteins are embedded in a lipid matrix whose specific characteristics play important roles in membrane protein function. Direct, specific interactions between a particular lipid (e.g. phosphoinositides or cholesterol) and protein have been widely characterized; in contrast, the effects of bulk material properties of the membrane, such as hydrophobic thickness or curvature stress are less well understood
- Ongoing project #5: How do cell-specific membrane environments affect membrane protein (GPCR, Akt, TRKs) signaling?
- Ongoing project #6: Discovering inhibitors that target microdomain affinity of transmembrane protein