Imaging Membrane Lipids During Neurodegeneration

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The plasma membrane of cells, composed mainly of lipids, is a fluid dynamic structure that has the ability to change its composition and density to adjust and react to its external environment. One way to do this is through the formation of specialized membrane micro domains called lipid rafts. Due to their variability of structure, imaging lipids (and lipid rafts) have posed a challenge, especially when trying to detect them by using standard imaging methods. Therefore this proposal will employ novel and innovative methodology to detect and characterize the composition membrane lipids, including those present in lipid rafts. This proposal will further characterize how membrane lipid composition changes in response to different neuro-toxic stimuli and will correlate shifting membrane composition with vulnerability to neuron cell death. Here we propose two innovative means of imaging components of neuronal membrane lipids in vitro and in vivo models of brain injury with the following specific aims: (1) Examine the response of lipid raft domains following stress in vitro and (2) Image gangliosides and other sphingolipids within lipid raft domains using imaging mass spectrometry. Both these aims are achievable and can be completed within the 5 year time-frame of an NSERC Discovery Grant. MSI is a relatively new imaging technique, and although there are several Canadian intuitions using MALDI-TOF analysis of samples, very few are using MALDI-TOF to image lipids in situ. We feel this is a distinct advantage of this NSERC Discovery Grant proposal. The impact of this research program will extend beyond the findings from our laboratory. We hope to build a strong rationale for the use of these imaging techniques, especially with respect to IMS and make them available to the University community. This will provide a physical source where scientific synergy can take place among different research groups. We feel that the impact of this research program will also be felt through the exceptional training potential of highly qualified personnel. By providing a unique training environment where trainees can learn both in vitro and in vivo techniques, we will provide a solid foundation of training and support to help them become successful.