ICAL: Impact of Cannabinoids Across Lifespan: Analytical Core

项目摘要：分析核心 拟议的NIDA英才中心，题为大麻类物质对寿命的影响(ICAL)， 将检验内源性大麻素(ECB)系统在体内非生理性激活的假设 青春期启动了对控制这一过程的遗传和表观遗传过程的重新编程 系统的分子结构、神经解剖结构和突触功能，最终 在认知和动机行为上产生持续的异常。为了检验这一假设，ical 将部署一种垂直整合的战略，将分子、神经解剖学、电生理、 和行为方法。分析核心将利用当代的液相色谱/质谱仪 光谱分析(LC/MS)方法以实现两个具体目标：目标1：为 ICAL的动物核心。与动物核心密切合作，分析核心将携带 开展药物代谢和药代动力学(DM-PK)研究，确保THC治疗 Ical(A)采用的方案在各种不同的系统暴露水平上产生一致的水平。 正在调查的试验组(青春期和成年期小鼠和两性大鼠)；(B) 药理上的相关性(即产生分级的和确定的CBR依赖的中毒程度)； 以及(C)考虑到新陈代谢以及脂质的蓄积和渗漏- 丰富的组织(如白色脂肪)。目标2：为医学项目提供生物分析支持。即使 ICIC的分子、突触和行为项目将并行推进，每个项目都将针对特定的 这些问题将需要欧洲央行对脑组织进行量化。分析核心将实现这一重要的 实验需要。其主任法兹·艾哈迈德博士将承担以下主要责任：(A) 实施LC/MS方法测定血液和其他组织中的THC及其代谢物； (B)采用LC/MS方法对欧洲央行大脑中的脂质进行定量分析；。(C)时间表 共享使用和维护LC/MS仪器：(D)监督高级工作人员的研究 助理(待定；25%努力)，负责样品准备；和(E)培训毕业生 在校学生和博士后学者使用LC/MS仪器。总而言之，协作工作 有了动物核心，分析核心将产生一套系统的强大的药效学 以及DM-PK数据，将允许开发和实施药理学和 翻译上相关的THC治疗方案。

PROJECT SUMMARY: ANALYTICAL CORE The proposed NIDA Center of Excellence, entitled Impact of Cannabinoids Across the Lifespan (ICAL), will test the hypothesis that non-physiological activation of the endocannabinoid (ECB) system in adolescence initiates a reprogramming of the genetic and epigenetic processes that govern this system’s molecular structure, neuroanatomical architecture, and synaptic functions, ultimately producing persistent abnormalities in cognition and motivated behavior. To test this hypothesis, ICAL will deploy a vertically integrated strategy combining molecular, neuroanatomical, electrophysiological, and behavioral approaches. The Analytical Core will utilize contemporary liquid chromatography/mass spectrometry (LC/MS) methods to achieve two specific aims: Aim 1: To provide analytical support to ICAL’s Animal Core. Working in close collaboration with the Animal Core, the Analytical Core will carry out drug metabolism and pharmacokinetics (DM-PK) studies to ensure that the THC treatment regimens employed by ICAL (a) produce consistent levels of systemic THC exposure across the various experimental groups under investigation (adolescent and adult mice and rats of both sexes); (b) are pharmacologically relevant (i.e., produce graded and defined degrees of CBR-dependent intoxication); and (c) take into consideration THC metabolism as well as accumulation in, and leakage from, lipid- rich tissues (e.g. white adipose). Aim 2: To provide bioanalytical support to ICAL projects. Even though ICAL’s Molecular, Synaptic and Behavioral Projects will advance in parallel, each will address specific questions that will require ECB quantification in brain tissue. The Analytical Core will fulfill this important experimental need. Its director, Dr. Faizy Ahmed, will have the following primary responsibilities: (a) implement LC/MS methods for the determination of THC and its metabolites in blood and other tissues; (b) implement LC/MS methods for the quantitative analysis of ECB lipids in the brain; (c) schedule shared use and maintenance of LC/MS instrumentation: (d) supervise a Senior Staff Research Associate (TBN; 25% effort) who will be responsible for sample preparation; and (e) train graduate students and post-doctoral scholars in the use of LC/MS equipment. In sum, working in collaboration with the Animal Core, the Analytical Core will generate a systematic set of robust pharmacodynamics and DM-PK data that will permit the development and implementation of pharmacologically and translationally relevant THC treatment protocols.