NHMRC Research Fellowship (SRFB): Vesicular trafficking pathways underpinning neuronal secretion and survival (2014–2018)
A SRFB would allow me to capitalise on the recent expansion of my research program to address the following fundamental questions: 1) How do secretory vesicles (SVs) find their way to the plasma membrane? We will determine how neurosecretory cells spatially adjust their vesicle pools to replenish those that have undergone fusion. We have identified a novel role for Myosin-6 in this process and will explain how actin and microtubules couple secretory vesicle replenishment with secretagogue stimulation. 2) How do SVs become fusion-competent? We will mainly focus on the role played by Munc18 in priming. We now have the tools, funding and preliminary data to unravel the selective contribution of Munc18 to priming. 3) How are the SVs segregated from retrograde vesicular cargoes in the crowded environment of the presynaptic nerve terminal? In nerve
terminals, the correct sorting of retrogradely targeted cargoes is ccurately and efficiently accomplished despite the considerable concomitant local recycling of synaptic vesicles. Uncovering the molecular mechanisms underpinning the regulation of presynaptic sorting and retrograde transport of membrane vesicles is critical for understanding normal neuronal development, plasticity and survival. 4) What drives the formation of a retrograde vesicle? We currently use time-lapse imaging of retrograde trafficking in microfluidic chambers
to pinpoint the role of critical presynaptically enriched proteins in orchestrating the retrograde trafficking essential for neuronal survival. 5) Clinical translation of our research findings. By blocking the exit from the Golgi complex of tumour necrosis factor cargoes in microglia, we can harness neuroinflammation and protect the brain from the devastating effects of stroke. We will also test this strategy in other
neurodegenerative mouse models including Alzheimer¿s disease.