Optoanesthesia

描述（由申请人提供）：烷基酚麻醉剂丙泊酚每年用于数百万例外科手术和有害手术。虽然异丙酚的临床应用已经扩大，但对其许多作用的机械理解在各个层面上都落后了。在这个提议中，我们将部署我们的丙泊酚的光敏烷基酚类似物，azi-propofol-m（aziPm）和2-丙炔氧基甲氧基-5-三氟甲基二氮杂环丙烯基苯酚（aziPm-click），在一系列分层研究中揭示：使用最先进的质谱和富集方法的光敏烷基酚结合蛋白质组（AIM 1），光活性烷基酚在脑切片离散核团中的电生理特性（AIM 2），以及个体细胞和网络对烷基酚催眠作用的体内贡献。这些后面的研究将使用光纤激光刺激活体小鼠脑的离散区域后，全身给予光敏烷基酚（目的3）。这三个目标是集成了他们的共同预测的分子底物所产生的非常不同的，互补的和公正的方法。这些研究将导致识别烷基酚作用的新型和合理的分子底物，这将作为随后涉及构建转基因动物的建议的验证基础。这个合作项目非常适合将Kelz实验室的神经生物学专业知识与Beck实验室的电生理学掌握以及Eckenhoff和Dailey实验室的生物化学能力相结合。

DESCRIPTION (provided by applicant): The alkylphenol anesthetic propofol is used in millions of surgical and noxious procedures annually. While the clinical use of propofol has swelled, mechanistic understanding of its many actions, on all levels, has lagged behind. In this proposal, we will deploy our photoactive alkylphenol analogues of propofol, azi-propofol-m (aziPm) and 2-propynloxymethoxy-5-trifluoromethyldiazirinylphenol (aziPm-click), in a tiered series of studies to reveal: the photoactive alkylphenol binding proteome using state-of-the-art mass spectrometry and enrichment methods (aim 1), the electro- physiological character of photoactive alkylphenols in discrete nuclei in brain slices (aim 2), and the in-vivo contribution o individual cells and networks to the hypnotic effects of alkylphenols. These latter studies will us fiberoptic laser stimulation of discrete regions of brain in live mice after systemic administratio of photoactive alkylphenols (aim 3). The three aims are integrated by their common prediction of molecular substrates arising from very different, complimentary and unbiased approaches. These studies will result in the identification of novel and plausible molecular substrates for alkylphenol action, which will serve as the basis for validation in subsequent proposals involving the construction of genetically altered animals. This collaborative project is ideally suited to integrate the neurobiological expertise of the Kelz lab with the electrophysiologic mastery of the Beck lab, and the biological chemistry prowess of the Eckenhoff and Dailey labs.