Regulation of Motile Cilia by (Phyto)Ceramide

Overview: Page A Title: Regulation of motile cilia by (phyto)ceramide Senior Personnel: Erhard Bieberich (P.I., Georgia Regents University) Guanghu Wang (Georgia Regents University) Ceramide is a sphingolipid that has mostly been implicated as cell signaling lipid for the induction of apoptosis. The P.I.’s laboratory has begun, for the first time, to define its unique and essential role in ciliogenesis. In the previous study, the P.I. has found that ceramide is enriched in a compartment at the base of primary cilia and that the interaction of ceramide with atypical PKC (aPKC) is critical for ciliogenesis in mammalian cells. New data suggest that regulation of primary and motile cilia by ceramide is evolutionarily conserved and involves phytoceramide and ceramide as determined with Chlamydomonas and ependymal cells, respectively. Our experiments will define lipid species critical for ciliogenesis in Chlamydomonas and mammalian cells (Aim 1), determine ceramide-interacting proteins and their function in intraflagellar transport (IFT) and length regulation (Aim 2); and test the significance of ceramide for cilium function in vivo using mouse models for ceramide deficiency (Aim 3). These experiments will address the P.I.’s long-term goal to define ceramide-regulated mechanisms that are essential for cilium biogenesis and function. Intellectual Merit : Primary and motile cilia are protrusions of the cell membrane with sensory and motor function, respectively. It is still not fully understood which factors regulate ciliogenesis. The concept that ceramide is enriched in a specialized, ciliogenic compartment and that ciliogenesis is regulated by a ceramide-induced ciliogenic lipid-protein complex associated with this compartment is absolutely novel and original. Broader Impacts : Because most mammalian cells have cilia, results from testing of the P.I.’s concept will significantly advance our knowledge across different research fields, including embryology, neurobiology, wound healing and biology of epithelial cells, and stem and cancer cell biology. The concept of a ceramide-induced lipid-protein complex defines the function of this lipid in a testable biological context (ciliogenesis). Therefore, this study opens up a new research field in defining the biological function of lipid-protein interaction. Methods and results obtained from this study will go beyond ceramide and will be applicable to other lipids with cell signaling activity. The proposed study will foster the academic career of at least two graduate students and is fully integrated into the undergraduate student programs at Georgia Regents University. These programs encourage students from the neighboring institutions, in particular Paine College, a community college with primarily students from minority groups, to participate in the P.I.’s research and to explore academic careers in biosciences. In addition, the P.I. organizes art-science workshops teaching young students of the elementary to high school level and their parents evolutionary concepts in biology by using clay to sculpt cells and organelles. Keywords: cilia, ceramide, sphingomyelinase, Chlamydomonas, ependymal, IFT, brain, development