Enhancing Glutamate Transport in Age-related Cognitive Decline and Alzheimer's Disease

增强谷氨酸转运以治疗与年龄相关的认知衰退和阿尔茨海默病

• 批准号: 9228807
• 负责人: Ana C. Pereira
• 金额: $ 16.8万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228807
• 关键词: Adult; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; American; Amino Acid Neurotransmitters; Amyloid beta-Protein; Area; Award; Behavior; Behavioral; Behavioral Assay; Biology; Brain; Cerebrum; Cognitive deficits; Data; Data Set; Dendritic Spines; Development; Disease; Electron Microscopy; Electrophysiology (science); Enhancers; Excitatory Amino Acids; Excitatory Synapse; FDA approved; Fostering; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genomics; Glutamate Transporter; Glutamates; Goals; Health; Hippocampal Formation; Hippocampus (Brain); Human; Impaired cognition; Impairment; Incidence; Instruction; Intervention; K-Series Research Career Programs; Knockout Mice; Leadership; Learning; Link; Long-Term Depression; Long-Term Potentiation; Measures; Medical; Memory; Memory Loss; Memory impairment; Mental Depression; Mentors; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Neurosciences Research; Pathogenesis; Pathway interactions; Performance; Physicians; Physiological; Play; Population; Predisposition; Prevention; Public Health; Rattus; Research; Research Personnel; Research Project Grants; Resolution; Riluzole; Risk Factors; Rodent; Role; Scientist; Societies; Structure; Synapses; Synaptic Transmission; System; Testing; Toxic effect; Training Activity; Transgenic Organisms; Translational Research; Validation; Wild Type Mouse; Work; age related; aged; aging brain; career; career development; design; drug development; effective therapy; empowered; excitotoxicity; experience; innovation; leadership development; mortality; mouse model; neural circuit; neuron loss; neurotransmission; new therapeutic target; novel; novel therapeutics; postsynaptic; prevent; professor; psychologic; public health relevance; relating to nervous system; skills; therapeutic target; tool; transcriptome sequencing; translational neuroscience; uptake

PROJECT SUMMARY: The long-term objective of the Paul B. Beeson Emerging Leaders Career Development Award in Aging (K76) is to support the development of the candidate into a leading physician-scientist in translational neuroscience of Aging and Alzheimer's disease (AD). The proposed K76 award will enable the candidate to develop the skills necessary to design and conduct multi-modal scientifically rigorous studies to advance our understanding of the pathophysiology of Aging and AD that will have a significant impact in the field. This overall objective will be accomplished through a structured, supervised research experience along with formal didactic instruction focused on (1) neurobiology of aging, AD, and glutamatergic neural systems, (2) structural brain analysis with electron microscopy, (3) genomics and (4) leadership development. AD is a serious public health concern associated with significant morbidity and mortality. There is a compelling need for studies that offer the possibility to advance the neurobiological understanding of AD and aging, which is AD's major risk factor, and the development of novel targets and more effective treatments. The neural circuits affected in aging and in AD are similar, involving the glutamatergic connections among cortical areas and with the hippocampal formation. In aging, synaptic changes occur with minimal neuronal death while in AD, there is frank loss of neurons. With the goal of further understanding the susceptibility of glutamatergic neural circuits to aging and AD that culminates in cognitive decline, the proposed project utilizes a multi-dimensional investigative approach focusing on the major glutamate transporter in the brain, EAAT2. EAAT2 plays a critical role in determining glutamate levels synaptically and extrasynaptically, and regulating physiological glutamatergic neurotransmission, that all are critical for learning, memory, and synaptic health. Importantly, EAAT2 activity is significantly decreased in both aging and AD, and associated with neurodegeneration in the latter. This proposal investigates EAAT2's pathophysiological role in aging and AD by, first, quantifying changes at the synaptic level, with correlative behavioral assays, and gene expression profiles in aging and AD mouse models, and second, with an intervention with an EAAT2-enhancer, the glutamate modulator riluzole. Moreover, this proposal uses a newly developed conditional EAAT2 knock-out (KO) mouse for further mechanistic studies on EAAT2's impact on gene expression patterns and behavior in the aging brain. These integrated aims will delineate the biology of EAAT2 in aging and AD brains at the structural, molecular and functional levels and will test EAAT2 enhancement as a therapeutic target for age- related cognitive decline and AD. This proposal builds on PI's recent work on glutamatergic dysregulation in the vulnerable excitatory synapses in aging and AD, her outstanding leadership skills and on the very extensive experience by mentors in structural brain analysis (such as electron microscopy), neurobiology of aging, AD, and glutamatergic neural systems. The applicant has assembled a preeminant and complementary group of mentors with the relevant expertise, including Professors Bruce McEwen, John Morrison, Patrick Hof and Paul Rosenberg, to guide her research project, and to supervise her career development and training activities. In summary, the proposal utilizes a multimodal and integrative investigative approach to test an innovative mechanistic hypothesis that can ultimately result in identification and validation of novel targets and development of effective treatments to age-related cognitive decline and AD, which remain thus far unmet medical needs. Importantly, the skills and data acquired during the K76 award period will provide the candidate with the tools required to achieve the long-term goal of becoming an independent and leader investigator in translational neuroscience research of aging and AD.

项目摘要： 保罗·B·比森（Paul B. Beeson）新兴领导者职业发展奖（K76）的长期目标是 支持候选人的发展为领先的医师科学家的转化神经科学。 衰老和阿尔茨海默氏病（AD）。拟议的K76奖将使候选人能够发展技能 设计和进行多模式的科学严格研究所必需的，以促进我们对 衰老和AD的病理生理学将对该领域产生重大影响。这个整体目标将是 通过结构化的，有监督的研究经验以及正式的教学教学完成 专注于（1）衰老，AD和谷氨酸神经系统的神经生物学，（2）结构性大脑分析 电子显微镜，（3）基因组学和（4）领导力发展。广告是一个严重的公共卫生问题 与明显的发病率和死亡率相关。有令人信服的研究需要 推进对AD和衰老的神经生物学理解的可能性，这是AD的主要危险因素，以及 新型目标和更有效的治疗方法的发展。 在衰老和AD中受影响的神经回路相似，涉及谷氨酸能连接 皮质区域以及海马形成。在衰老中，最小神经元发生突触变化 在广告中死亡，神经元坦率地丧失。目的是进一步了解 拟议项目利用谷氨酸能神经回路，达到认知能力下降的衰老和广告 一种多维调查方法，重点是大脑中主要的谷氨酸转运蛋白，EAAT2。 EAAT2在突触和间外确定谷氨酸水平和调节方面起着关键作用 生理谷氨酸能神经传递，这对于学习，记忆和突触健康至关重要。 重要的是，衰老和AD的EAAT2活性都显着降低，并且与 后者的神经变性。该提案调查了EAAT2在衰老和AD中的病理生理作用 首先，使用相关行为测定和基因表达来量化突触水平的变化 衰老和AD鼠标模型中的轮廓，其次，与EAAT2-Enhancer进行干预， 谷氨酸调节剂riluzole。此外，该提案使用新开发的有条件的EAAT2淘汰赛 （KO）小鼠，以进一步研究EAAT2对基因表达模式和行为的影响 衰老的大脑。这些综合目的将描述EAAT2在衰老和广告大脑中的生物学 结构，分子和功能水平，将测试EAAT2增强，作为年龄的治疗靶标 相关的认知下降和广告。该提案是基于Pi最近的有关谷氨酸能失调的工作 脆弱的兴奋性突触在衰老和广告中，她出色的领导能力以及 导师在结构性大脑分析（例如电子显微镜）中的丰富经验，神经生物学 衰老，AD和谷氨酸能神经系统。申请人已经组装了盛大和互补的 相关专业知识的一群导师，包括布鲁斯·麦克尤恩教授，约翰·莫里森，帕特里克·霍夫 保罗·罗森伯格（Paul Rosenberg）指导她的研究项目，并监督她的职业发展和培训 活动。 总而言之，该提案利用多模式和综合调查方法来测试创新 机械假设最终可能导致对新目标的识别和验证 开发与年龄相关的认知下降和AD的有效治疗 医疗需求。重要的是，K76奖励期间获得的技能和数据将为候选人提供 凭借实现长期目标的工具，成为成为独立和领导者的研究者 衰老和AD的转化神经科学研究。