Retinal degenerative diseases such as macular degeneration involve progressive dysfunction and deterioration of rod and cone photoreceptors. In these and other neurodegenerative diseases, neurons post-synaptic to the deteriorating cells are believed frequently to preserve their capacity for neural signaling; functional loss follows from the inability of the deteriorating pre-synaptic cell to stimulate the post-synaptic membrane receptor protein of a specific chemical synapse. Here we propose a novel project, the long-term goal of which is to restore stimulus-regulated signaling at nonfunctioning chemical synapses. The proposed approach is to develop nanoscale neuromodulating platforms (NNPs) that are responsive to external stimulating signals and interact physiologically with specific post-synaptic membrane receptor proteins. The essential feature of the platform is electrochemical control of the accessibility, to the receptor protein, of neurotransmitter derivatized and tethered to a signal-responsive substrate. In the first three years of the project we propose to construct and test prototype platforms (surface dimensions of ~0.1-1 mm) that, in response to light, modulate the electrophysiological activity of defined membrane receptor proteins (e.g., GABAc receptors) expressed in Xenopus oocytes. The platform's active surface will consist of alkyl and poly(ethylene oxide) chains that are covalently linked to the surface, derivatized with a ferrocene/ferricinium moiety, and distally terminated by an N-substituted analog of the relevant amino acid neurotransmitter. The analog's accessibility to the receptor protein will be regulated by an avalanche photodetector (APD) architecture of the platform, resulting in redox-control of the hydrophobicity of the ferrocene/ferricinium and a conformational change in the tethering chain.
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