The nano-meter scale organization and function of phosphoinositide signaling at central synapses
1) Lipid signaling plays an essential role in synaptic transmission and aberrant lipids signaling has been implicated in many brain diseases including AD, Down’s syndrome and epilepsy; however, we know very little about how lipids works at nanometer scales in the plasma membrane of neurons. We propose to develop and apply innovated super-resolution optical imaging to map the molecular topography of these key signaling molecules (PI(4,5)P2 and syntaxin1A) at nerve terminal membrane at nanometer precision. The proposed research will have a profound impact on synaptic biology and neuron communication. It will also have broad medical relevance beyond the cell biology of neurons, and help to develop better therapeutic rationales for a few complex brain diseases mentioned above.
2) We will establish a novel super-resolution optical imaging approach for lipid signaling study at nanometer precision, which improves the spatial resolution of imaging ~10 times compared with other modern lightmicroscopy including confocal, two-photon or TIRF microscopy. This will open a new avenue toward cellular and molecular neuroscience. The novel approaches to acute manipulate local PIs in the PM of live cells may have broader application in the other relevant fields of lipid signaling. Preliminary data generated from this study will be critical for a successful federal project (RO1 or NSF).