Interests and Current Projects
The ability to change shape and move is critical for the function of cell types ranging from single celled amoeba to immune cells and neurons. Similarly, the ability of organelles to change shape and move plays an essential role in intracellular transport. We are studying the engine that controls cell and organelle shape and movement, the actin cytoskeleton, using a combination of cell biological, biochemical and genetic methods. We are working to determine how actin filament assembly is initiated, how it is regulated, and how it functions during processes such as whole cell migration and membrane trafficking. Moreover, we are working to understand how diverse bacterial and viral pathogens target the actin cytoskeleton of host cells to promote pathogen internalization, replication and spread during infection.
Regulation of actin assembly in intracellular trafficking and cell migration.
A key control point in actin assembly is the initiation of new filament formation by a processes called nucleation. Work from our lab and others established that the Arp2/3 complex is a critical actin nucleating factor that also organizes filaments into Y-branched networks. The activity of the Arp2/3 complex is in turn regulated by a family of proteins called nucleation promoting factors (NPFs), which are themselves controlled by signaling proteins and lipids. We are working to understanding how NPFs activate the Arp2/3 complex to form diverse actin-containing structures in association with the plasma membrane and organelle membranes. Our current emphasis is on characterizing NPFs that function in membrane trafficking and nuclear processes, and assessing their role in cell polarization and migration.
Interaction between pathogens and the host actin cytoskeleton.
An amazing variety of bacterial and viral pathogens target the actin cytoskeleton of host cells during infection. To gain broad insight into the strategies used by pathogens to exploit actin, we study diverse bacterial pathogens including Rickettsia, Burkholderia, and Mycobacterium species, as well as the insect virus baculovirus. We working to understand how pathogen proteins target host cell signaling, cytoskeletal, membrane trafficking, and gene regulatory proteins to promote invasion, intracellular replication, motility, and cell-cell spread. By studying the interaction between diverse pathogens and actin, we hope to gain insights into critical mechanisms of pathogenesis as well as the normal functions of the cytoskeleton in uninfected cells.
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Developing drugs that target the cytoskeleton of parasites.
Parasites called trypanosomes cause neglected diseases that affect millions of the poorest people in the world. Because they rely on the cytoskeleton to complete essential processes, trypanosomes are vulnerable to attack by drugs that target cytoskeletal proteins. We are working to identify a new class of anti-trypanosomal agents that targeting kinesins and myosins, large superfamilies of molecular motor proteins that move cargo along cytoskeletal filaments. We are pursuing a multidisciplinary strategy that makes use of chemical biology, molecular biology and cell biology methods to analyze the basic processes that require motor function and to identify lead compounds to pursue in drug development efforts.