Mitochondrial, antioxidant and cognitive effects of Centella asiatica during aging

 描述（由申请人提供）：该提案概述了一项研究和职业发展计划，该计划建立在Gray博士现有培训的基础上，并使她能够：1）获得体外和体内方法的专业知识，以研究认知障碍的神经生物学; 2）获得线粒体研究技术和进展的详细知识; 3）巩固技能，以表征植物产品，并进行严格的补充和替代医学研究;和4）建立和加强所需的成功作为一个独立的调查员的技能。格雷博士的优秀导师和协作培训团队都位于俄勒冈州健康与科学大学（OHSU），使其成为该奖项K99阶段的理想场所。除了提供世界一流的基础和转化研究技术培训外，OHSU还提供许多课程和研讨会，以加强沟通，领导和授予写作能力，这对于实现她对神经活性植物和饮食干预进行独立研究的长期职业目标至关重要。 本研究的目的是确定药用植物积雪草（Centella asiatica（L.）Urban（CA）调节线粒体功能和抗氧化反应以引起其神经保护和认知增强作用。CA是一种阿育吠陀草药，用于改善认知功能，这一效果得到了人类和许多啮齿动物模型研究的支持。我们的实验室已经表明，CA水提取物（CAW）可以改善老年野生型小鼠以及Tg 2576小鼠（β-淀粉样蛋白（A β）积累的阿尔茨海默病（AD）模型）的学习和记忆，并保护神经母细胞瘤细胞免受A β诱导的细胞死亡。我们的初步体外和体内数据表明，CAW激活内源性抗氧化反应途径，诱导线粒体生物合成。该提案将确定这些途径中的每一个如何有助于CAW的神经保护和认知增强作用。在目标1中，Gray博士将接受培训，并应用原代神经元细胞培养的更具生理相关性的体外模型系统，以确定CAW保护免受阿托伐他汀毒性的分子机制。在目标2中，将学习一系列行为评估，并用于确定CAW改变了认知的哪些方面，以及其抗氧化剂和线粒体效应如何有助于这些认知增强效应。目标2还将通过评估长期CAW治疗的认知效应和潜在机制来探索CAW的预防潜力。 这项工作将解决我们对CAW机制的理解中的关键空白，以及线粒体和抗氧化剂途径如何相互作用并参与使用强大的AD体外和体内模型调节神经元健康和认知。本文建立的结果和技术将有助于确定未来在AD a以及其他认知障碍疾病的背景下使用植物或膳食制剂进行治疗干预的特定靶点，并将导致更好的临床试验 这样的治疗。K99奖提供的技能和培训将启动格雷博士积极，独立的研究生涯。

 DESCRIPTION (provided by applicant): This proposal outlines a research and career development plan that builds on Dr. Gray's existing training and allows her to: 1) gain expertise with in vitro and in vivo methods to study the neurobiology of cognitive impairment; 2) acquire detailed knowledge of techniques and advances in mitochondrial research; 3) solidify skills to characterize botanical products and perform rigorous complementary and alternative medicine research; and 4) build and strengthen the skills needed for success as an independent investigator. Dr. Gray's superb mentorship and collaborative training team are all located at Oregon Health and Science University (OHSU) making it an ideal setting for the K99 phase of this award. In addition to providing world-class training in basic and translational research techniques, numerous courses and seminars are available at OHSU to strengthen the communication, leadership and grant writing capabilities essential for achieving her long-term career goal of conducting independent research on neurologically active botanical and dietary interventions. The goal of the proposed research is to determine how the medicinal plant Centella asiatica (L.) Urban (CA) modulates mitochondrial function and antioxidant response to elicit its neuroprotective and cognitive- enhancing effects. CA is an Ayurvedic herb used to improve cognitive function, an effect supported by studies in humans and numerous rodent models. Our lab has shown that CA water extract (CAW) can improve learning and memory in aged wild-type as well as Tg2576 mice, an Alzheimer's Disease (AD) model of beta- amyloid (Aß) accumulation, and protect neuroblastoma cells against Aß-induced cell death. Our preliminary in vitro and in vivo data show that CAW activates the endogenous antioxidant response pathway and induces mitochondrial biogenesis. This proposal will determine how each of those pathways contributes to the neuroprotective and cognitive-enhancing effects of CAW. In Aim 1 Dr. Gray will be trained in and apply the more physiologically relevant in vitro model system of primary neuronal cell culture to determine the molecular mechanism by which CAW protects against Aß toxicity. In Aim 2, a battery of behavioral assessments will be learned and used to determine which aspects of cognition are altered by CAW, and how its antioxidant and mitochondrial effects contribute to these cognitive-enhancing effects. Aim 2 will also explore the preventative potential of CAW by assessing the cognitive effects and underlying mechanisms of long-term CAW treatment. This work will address critical gaps in our understanding of the mechanism of CAW and how mitochondrial and antioxidant pathways interact and participate in modulating neuronal health and cognition using powerful in vitro and in vivo models of AD. The results and techniques established here will help identify specific targets for future therapeutic intervention with botanical or dietary agents in the context of AD a well as other conditions with cognitive impairment and will lead to better-informed clinical trials of such treatments. The skills and training provided by the K99 award will launch Dr. Gray's active, independent research career.