Nanoscale Analysis of Inter-Organelle Interactions and their Role in Neuronal Plasticity

ongoing

Cellular communication is mediated by nanometer-sized organelles (vesicles, stress granules, exosomes) that are potentially responsible for carrying and releasing signalling molecules. I propose to use my extensive background in electroanalytical chemistry and mass spectrometry imaging to develop new technologies to chemically dissect vesicles, exosomes, and stress granules both dynamically and in fixed samples with spatial discrimination across living cells - the next frontier in cell analysis. The following four aims are proposed. I will develop 1) methods to chemically dissect and dynamically determine chemical species at and in nanometer organelles and suborganelles, 2) methods to spatially measure and evaluate the chemistry of organelles across cells, 3) analytical approaches to measure exchange of transmitters and metabolites between organelles and the role of this exchange in cellular communication, and 4) experiments in organoids and fly brain leading to a unified theory of the chemical interaction between organelles involved in cellular communication and plasticity. My group has pioneered the discovery that most regular exocytosis is partial, adding a third release mode to kiss n run or full vesicle distention. This opens a window of discovery concerning the structural and dynamical mechanisms of organelles that regulate neural communication. Ultimately, this will allow me to discern the chemical mechanisms of initial plasticity and brain cellular disease as it is likely that the different organelles in the cell related to communication interact chemically to regulate this process. This proposal is to develop and apply analytical methods to discover the interconnections between these organelles, and to relate them to the chemical events initiating plasticity.