Development of Nanoscale Neuromodulationg Platforms

描述：（申请人的摘要）视网膜变性疾病，例如 黄斑变性涉及进行性功能障碍和视杆细胞退化 和视锥细胞。在这些和其他神经退行性疾病中， 突触后退化的细胞被认为经常保存 他们的神经信号的能力;功能丧失， 来刺激突触后膜 一种特殊化学突触的受体蛋白。在这里，我们提出一个小说 该项目的长期目标是恢复刺激调节信号 不起作用的化学突触建议的方法是发展 纳米级神经调节平台（NNPs），其响应于外部 刺激信号，并与特定的突触后神经元相互作用。 膜受体蛋白该平台的基本特征是 电化学控制的可及性，受体蛋白， 神经递质衍生化并拴系到信号响应底物上。在 在项目的前三年，我们建议建造和测试原型 平台（表面尺寸约0.1-1 mm），响应于光， 调节确定的膜受体的电生理活性 蛋白质（例如，GABAc受体）在非洲爪蟾卵母细胞中表达。平台的 活性表面将由烷基和聚（环氧乙烷）链组成， 共价连接到表面，用二茂铁/铁离子衍生 部分，并通过相关的N-取代的类似物末端 氨基酸神经递质类似物对受体蛋白的可及性 的雪崩光电探测器（APD）架构进行调节。 平台，导致氧化还原控制的疏水性 二茂铁/铁离子和系链中的构象变化。

DESCRIPTION: (Applicant's Abstract) 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.