Current Research and Scholarly Interests
A decade ago, a collection of multi-organ pediatric disorders was attributed to dysfunctional cilia; cell-surface organelles that mediate cell-to-cell communication. These disorders (termed ciliopathies) predispose patients to respiratory inflammation, diabetes, and cancer, and the elucidation of cilia functions inform these prevalent health problems. Reflecting the diverse symptoms of cilia diseases, cilia function throughout the body, and surprisingly, almost every cell type presents at least one cilium. Cilia house receptors and receive signals, but it is not known how signaling is regulated or transduced into the cell. Receptor trafficking provides a molecular entry point to this problem as the receptor mistrafficking is characteristic of ciliopathies. The goal of my research is to determine how receptor trafficking regulates cilia signaling, and to uncover novel roles of cilia in cell-to-cell communication.
1. Receptor Trafficking and Bardet-Biedl Syndrome
The ciliary membrane contains numerous G-protein coupled receptors (GPCRs) that, upon activation, are removed from the cilium. By live-cell imaging of ciliated epithelial cells, I found that two competing pathways remove activated GPCRs from cilia: retrieval back into the cell or secretion into extracellular vesicles. Importantly, in the ciliopathy Bardet-Biedl Syndrome (BBS), both pathways are misregulated. One branch of my research focuses on how BBS-associated proteins regulate receptor trafficking, and how receptor trafficking regulates signaling.
2. Biogenesis of Extracellular Vesicles
A second thrust of my research is to understand how extracellular vesicles are formed. Extracellular vesicles are widely observed in biology, and function both to dispose unwanted molecules and transfer messages to other cells. Mammals release extracellular vesicles by several distinct pathways, yet our molecular understanding is limited to highly-conserved components identified by yeast genetics. Although yeast genetics discovered the important ESCRT cascade, mammals have elaborated and, in some contexts deviated from, this mechanism. For instance, mammalian cells have evolved to use actin for releasing vesicles from cilia, microvilli, and the plasma membrane. Leveraging biochemical tools for studying cilia, I identified a network of actin motors (Myosin 6) and crosslinkers (Drebrin, alpha-Actinin-4) that sever extracellular vesicles from cilia. This research informs how mammals produce extracellular vesicles, and provides molecular tools to determine the physiologic functions of extracellular vesicles.