Integration of transcriptomic and metabolomic analysis of the effects of Centella asiatica in cortical neurons

项目概要_总体 与衰老有关的挑战，包括情绪的改变、睡眠障碍和认知能力的下降， 对老年人的生活质量产生不利影响。许多植物制剂据称可以提高恢复力 这些变化，但很少有在精心设计的临床试验中进行评估。一个理想的临床试验将使用 一种针对其活性成分进行优化的产品，并研究植物学的适当措施， 在相关目标人群中的疗效。因此，需要进行合理的临床前研究，以确定 植物的作用，这些作用的机制，以及植物化学成分的调节 这些过程。研究还应确定植物不同成分之间的相互作用， 植物的靶向接合的生物标志物，化合物在体内的分布，以及化合物的变异性。 不同人群的反应，例如年龄或性别群体。建议的植物性膳食补充剂 研究中心（BDSRC）将建立一个实验方法和技术的管道， 提供这些关键问题的答案，重点是“植物药增强神经和功能 在老化的韧性”。这一研究平台将用于巩固和扩大我们广泛的初步 对积雪草（CA;“gotu kola”）的研究，为老年参与者的临床试验做准备。第二 植物，睡茄（WS;“ashwagandha”），与令人信服的报告类似的生物效应CA 将在研究管道的早期阶段进行审查。该中心的具体目标是：（1）确保 CA和WS的可靠供应，并开发针对其目标和非目标分析的方法。 植物提取物，血浆和脑组织中的成分;（2）研究CA的体内作用， 已知活性化合物对小鼠认知、睡眠障碍和情绪的影响，并鉴定体内生物标志物 （3）探讨CA和WS提取物的作用机制和活性成分， 靶向和非靶向方法，包括组合物的生物化学计量学相关性与生物 活性和代谢组学或转录组学。这些目标将由 植物核心的协同相互作用，研究项目1研究CA对认知的体内作用， 睡眠剥夺和情绪和研究项目2探索机制和活性化合物的CA和 WS使用体外小鼠原代神经元、离体小鼠脑切片和体内黑腹果蝇。一个 行政核心将协调、指导和传播BDSRC的研究活动，并提供 数据管理和统计支持。它还将协调目标（4），即提供研究培训 和职业发展机会的研究生和博士后科学家。BDSRC的管道 将来，将包括在OHSU的NIH/莱顿老龄化和阿尔茨海默病中心进行的临床试验。

PROJECT SUMMARY_OVERALL Aging- related challenges, including alterations in mood, sleep disturbances and cognitive decline, have detrimental effects on quality of life for the elderly. Many botanical agents are purported to improve resilience to these changes, yet few have been evaluated in well-designed clinical trials. An ideal clinical trial would use a product optimized for its active constituents, and investigate the botanical for appropriate measures of efficacy in a relevant target population. Sound preclinical research is therefore needed to identify the functional effects of a botanical, mechanisms underlying these effects, and the phytochemical constituents modulating these processes. Studies should also identify interactions between different constituents of botanical, in vivo biomarkers of target engagement by the botanical, distribution of the compounds in the body, and variability of response in different populations e.g. age or gender groups. The proposed Botanical Dietary Supplement Research Center (BDSRC) will establish a pipeline of experimental approaches and techniques required to deliver answers to these critical issues, with a focus on “Botanicals enhancing neurological and functional resilience in aging”. This research platform will be used to consolidate and expand our extensive preliminary studies on Centella asiatica (CA; “gotu kola”), in preparation for a clinical trial in aging participants. A second botanical, Withania somnifera (WS; “ashwagandha”), with compelling reports of similar biological effects to CA will be examined in earlier stages of the research pipeline. The specific aims of the Center are to (1) to ensure a reliable supply of CA and WS and develop methods for targeted and untargeted analysis of their constituents in plant extracts, plasma and brain tissue; (2) to investigate the in vivo effects of CA and currently known active compounds on cognition, sleep disturbance and mood in mice, and identify in vivo biomarkers relating to these effects; (3) to explore mechanisms and active compounds of CA and WS extracts through targeted and untargeted approaches including biochemometric correlations of composition with biological activity, and metabolomics or transcriptomics of treated target tissues. These goals will be achieved by the synergistic interaction of a Botanical Core, Research Project 1 examining in vivo effects of CA on cognition, sleep deprivation and mood and Research Project 2 exploring mechanisms and active compounds of CA and WS using mouse primary neurons in vitro, mouse brain slices ex vivo and Drosophila melanogaster in vivo. An Administrative Core will co-ordinate, guide and disseminate the research activities of the BDSRC, and provide data management and statistical support. It will also coordinate aim (4) which is to provide research training and career development opportunities to graduate students and postdoctoral scientists. The BDSRC’s pipeline will, in future, include clinical trials performed at the NIH/Layton Aging and Alzheimer’s Center at OHSU.