Mitochondrial, antioxidant and cognitive effects of Centella asiatica during aging

积雪草在衰老过程中的线粒体、抗氧化和认知作用

基本信息

批准号：
9762849
负责人：
Nora Gray
金额：
$ 23.48万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762849
关键词：
Acids Acute Address Age-Months Age-associated memory impairment Aging Alternative Therapies Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Antioxidants Attenuated Award Ayurvedic Medicine Basic Science Behavior assessment Behavioral Biochemical Pathway Bioenergetics Biogenesis Biological Models Botanicals Brain Cell Culture Techniques Cell Death Cell Line Chronic Clinical Trials Cognition Cognitive Communication Complementary and alternative medicine Data Development Development Plans Diet Dietary Intervention Elements Evaluation Exposure to Future Gene Expression Genes Goals Gotu kola Grant Health Health Sciences Herb Human Impaired cognition Impairment In Vitro Individual Knock-out Knowledge Leadership Learning Long-Term Effects Mainstreaming Medicinal Plants Memory Mentors Mentorship Methods Mitochondria Molecular Monitor Morphology Mus Neurobiology Neurodegenerative Disorders Neurologic Neurons Oral Administration Oregon Oxidative Stress Pathway interactions Phase Physiological Plants Play Reporting Research Research Personnel Research Technics Rodent Model Role Senile Plaques Slice Techniques Testing Tg2576 Therapeutic Therapeutic Agents Therapeutic Intervention Training Translational Research Triterpenes Universities Water Work Writing abeta accumulation abeta toxicity aged attenuation behavior test career career development cognitive enhancement cognitive function cohort executive function experimental study healthy aging improved in vitro Model in vivo in vivo Model inhibitor/antagonist insight interest mitochondrial dysfunction neuroblastoma cell neuron loss neurotoxicity new therapeutic target overexpression oxidative damage prevent public health relevance research and development response skills skills training success transcription factor

Acids Acute Address Age-Months Age-associated memory impairment Aging Alternative Therapies Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Antioxidants Attenuated Award Ayurvedic Medicine Basic Science Behavior assessment Behavioral Biochemical Pathway Bioenergetics Biogenesis Biological Models Botanicals Brain Cell Culture Techniques Cell Death Cell Line Chronic Clinical Trials Cognition Cognitive Communication Complementary and alternative medicine Data Development Development Plans Diet Dietary Intervention Elements Evaluation Exposure to Future Gene Expression Genes Goals Gotu kola Grant Health Health Sciences Herb Human Impaired cognition Impairment In Vitro Individual Knock-out Knowledge Leadership Learning Long-Term Effects Mainstreaming Medicinal Plants Memory Mentors Mentorship Methods Mitochondria Molecular Monitor Morphology Mus Neurobiology Neurodegenerative Disorders Neurologic Neurons Oral Administration Oregon Oxidative Stress Pathway interactions Phase Physiological Plants Play Reporting Research Research Personnel Research Technics Rodent Model Role Senile Plaques Slice Techniques Testing Tg2576 Therapeutic Therapeutic Agents Therapeutic Intervention Training Translational Research Triterpenes Universities Water Work Writing abeta accumulation abeta toxicity aged attenuation behavior test career career development cognitive enhancement cognitive function cohort executive function experimental study healthy aging improved in vitro Model in vivo in vivo Model inhibitor/antagonist insight interest mitochondrial dysfunction neuroblastoma cell neuron loss neurotoxicity new therapeutic target overexpression oxidative damage prevent public health relevance research and development response skills skills training success transcription factor

展开

项目摘要

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.

描述（由应用程序提供）：该提案概述了一项研究和职业发展计划，该计划基于格雷博士的现有培训，并允许她：1）通过体外和体内方法获得专业知识，以研究认知障碍的神经生物学； 2）获取有关线粒体研究技术和进步的详细知识； 3）巩固技能以表征植物产品并进行严格的完整性和替代医学研究； 4）建立和增强作为独立研究人员成功所需的技能。格雷博士的出色心态和协作培训团队都位于俄勒冈州健康与科学大学（OHSU），这是该奖项K99阶段的理想场所。除了提供基本和翻译研究技术的世界一流培训外，OHSU还提供许多课程和半段，以增强对实现对神经学活跃植物学和饮食干预措施独立研究的长期职业目标至关重要的沟通，领导和授予写作能力。拟议的研究的目的是确定药用植物Centella Asiatica（L.）Urban（CA）如何调节线粒体功能和抗氧化剂反应，以引起其神经保护和认知增强作用。 Ca是一种用于改善认知功能的阿育吠陀草药，这是由人类和众多啮齿动物模型的研究支持的。我们的实验室表明，CA水提取物（CAW）可以改善老年野生型和TG2576小鼠的学习和记忆，这是β-淀粉样蛋白（Aß）积累的阿尔茨海默氏病（AD）模型，并保护神经母细胞瘤细胞抗Aβ诱导的细胞死亡。我们的初步体外和体内数据表明，CAW激活内源性抗氧化剂反应途径并诱导线粒体生物发生。该提案将决定每种途径如何促进CAW的神经保护作用和认知增强作用。在AIM 1中，Gray博士将接受训练，并应用原代神经元细胞培养的体外模型系统更相关，以确定CAW可预防Aß毒性的分子机制。在AIM 2中，将学习和使用一系列行为评估，以确定CAW改变了哪些方面，以及其抗氧化剂和线粒体效应如何有助于这些认知增强作用。 AIM 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机制以及线粒体和抗氧化途径如何相互作用并参与使用AD的强大体外和体内模型调节神经元健康和认知的关键差距。此处建立的结果和技术将有助于确定在AD和其他患有认知障碍的情况下与植物或饮食剂进行未来治疗干预的特定目标，并将导致更明智的临床试验这样的治疗方法。 K99奖提供的技能和培训将启动Gray博士的活跃，独立的研究职业。