Development of Nanoscale Neuromodulationg Platforms

描述：(申请人摘要)视网膜退行性疾病，如 黄斑变性涉及进行性视杆功能障碍和恶化 和视锥感光器。在这些和其他神经退行性疾病中，神经元 不断恶化的细胞的突触后经常被认为保存 它们的神经信号传递能力；功能丧失是由于无法 不断恶化的突触前细胞刺激突触后膜 一种特定化学突触的受体蛋白。在这里，我们提议写一部小说 项目，其长期目标是恢复受刺激调节的信号 不起作用的化学突触。建议的方法是开发 对外界反应的纳米级神经调节平台(NNPs) 刺激信号和与特定突触后的生理相互作用 膜受体蛋白。该平台的基本特征是 对受体蛋白可及性的电化学控制 神经递质衍生并连接到信号反应底物上。在……里面 在项目的前三年，我们建议构建和测试原型 平台(表面尺寸约0.1-1毫米)，响应于光， 调节特定膜受体的电生理活动 在非洲爪哇卵母细胞中表达的蛋白质(如GABAc受体)。该平台的 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/铁衍生 部分，并由相关的N-取代类似物远端终止 氨基酸类神经递质。类似物对受体蛋白的可及性 将由雪崩光电探测器(雪崩光电探测器)架构进行调节 平台，导致氧化还原控制的疏水性 二茂铁/铁和链链上的构象变化。

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.