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.

项目概要： 保罗B的长期目标。Beeson Emerging Leaders Career Development Award in Aging（K76） 支持候选人发展成为转化神经科学领域的领先医生-科学家， 衰老和阿尔茨海默病（AD）。拟议的K76奖将使候选人能够发展技能， 有必要设计和进行多模式的科学严谨的研究，以促进我们对 衰老和AD的病理生理学，将在该领域产生重大影响。这一总体目标将是 通过结构化，监督研究经验沿着正式的教学指导完成 专注于（1）衰老，AD和神经系统的神经生物学，（2）结构脑分析， 电子显微镜，（3）基因组学和（4）领导力发展。AD是一个严重的公共卫生问题 与显著的发病率和死亡率相关。迫切需要进行研究， 有可能促进对AD和衰老的神经生物学理解，这是AD的主要风险因素， 开发新的靶点和更有效的治疗方法。 在衰老和AD中受影响的神经回路是相似的，涉及神经元之间的神经元连接。 皮质区和海马结构。在衰老过程中，突触发生变化， 死亡，而在AD中，有神经元的坦率损失。为了进一步了解 该项目利用了与衰老和AD相关的神经回路，这些神经回路最终导致认知能力下降， 一个多维度的研究方法，专注于大脑中的主要谷氨酸转运蛋白EAAT 2。 EAAT 2在突触和突触外决定谷氨酸水平以及调节谷氨酸水平中起关键作用。 生理学上的突触能神经传递，都是学习，记忆和突触健康的关键。 重要的是，EAAT 2活性在衰老和AD中均显著降低，并且与 神经退行性变在后者。该提案研究了EAAT 2在衰老和AD中的病理生理作用。 首先，通过相关的行为分析和基因表达来量化突触水平的变化， 第二，通过EAAT 2增强剂的干预， 谷氨酸调节剂利鲁唑。此外，该提议使用新开发的条件性EAAT 2敲除， (KO)EAAT 2对基因表达模式和行为的影响的进一步机制研究。 老化的大脑这些综合目标将描绘EAAT 2在衰老和AD大脑中的生物学， 结构，分子和功能水平，并将测试EAAT 2增强作为年龄- 相关认知能力下降和AD。这项建议是建立在PI最近对神经元代谢失调的研究基础上的。 衰老和AD中脆弱的兴奋性突触，她杰出的领导才能， 导师在脑结构分析（如电子显微镜）、神经生物学、 衰老、AD和神经系统的疾病。申请人已经组装了一个卓越的和互补的 一组具有相关专业知识的导师，包括布鲁斯·麦克尤恩教授、约翰·莫里森教授、帕特里克教授、霍夫教授 和保罗罗森伯格，指导她的研究项目，并监督她的职业发展和培训 活动 总之，该提案利用多模式和综合调查方法来测试一个创新的 机制假设，最终可以识别和验证新的目标， 开发有效的治疗方法，以治疗与年龄相关的认知衰退和AD，迄今为止尚未得到满足 医疗需求。重要的是，在K76奖励期间获得的技能和数据将为候选人提供 与所需的工具，以实现成为一个独立的和领导调查员的长期目标， 衰老和AD的转化神经科学研究。