Neuron cell death and synapse disruption seen during aging and in neurodegenerative diseases is a non-cell-autonomous process and involve a multi system progression. As neurons are highly polarized cells with very long axons, in order to remain healthy and function properly, they depend on accurate and efficient long-distance communication mechanisms. My long-term goal is to elucidate the molecular mechanisms for long distance signaling between neurons and their environment. I will combine state-of-the-art multidisciplinary approaches such as single molecule live imaging techniques, nanofluid-co-culture chambers and differential proteomics approaches on mouse model systems to address basic questions on the roles that retrograde signaling between muscle, glia and neurons play in cell survival and synapse stability.
We will develop a unique in vitro microfluidic platform with motor neuron cell bodies on one-side and glia/muscle cells on the other side, which will allow us to distinguish local versus long distance signaling mechanisms and monitor retrograde axonal transport, as well as to manipulate retrograde signaling pathway regulating NMJ maintenance and cell survival. Three approaches will be taken: 1. In vitro and in vivo live cell imaging. 2. Specific cell biology. 3. Functional proteomics. Using model systems for aging and for neurodegenerative diseases will allow us to characterize the vital signaling mechanisms for NMJ/synapse maintenance and neuronal survival, as well as reveal novel stress factors that lead to nerve degeneration and cell death. Using the above strategies will provide a clearer picture of how cells use spatial localization and transport to regulate cell survival and synapse stability. The research will generate novel insights into neurodegenerative mechanisms and, ultimately, provide a molecular basis for new drugs as well as delivery methods to treat a range of neurodegenerative diseases.
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