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： Paul B. Beeson 老龄化领域新兴领导者职业发展奖 (K76) 的长期目标是 支持候选人发展成为转化神经科学领域的领先医师科学家 衰老和阿尔茨海默病（AD）。拟议的 K76 奖项将使候选人能够发展技能 有必要设计和进行多模式科学严谨的研究，以增进我们对 衰老和 AD 的病理生理学将对该领域产生重大影响。这一总体目标将是 通过结构化的、受监督的研究经验以及正式的教学指导来完成 重点关注 (1) 衰老、AD 和谷氨酸神经系统的神经生物学，(2) 大脑结构分析 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 与显着的发病率和死亡率相关。迫切需要提供以下研究 促进对 AD 和衰老（AD 的主要危险因素）的神经生物学理解的可能性，以及 开发新的靶点和更有效的治疗方法。 衰老和 AD 中受影响的神经回路是相似的，涉及 皮质区域和海马结构。在衰老过程中，突触变化以最小的神经元发生 AD患者死亡时，神经元明显丧失。为了进一步了解其敏感性 谷氨酸能神经回路导致衰老和 AD，最终导致认知能力下降，该项目利用 一种多维研究方法，重点关注大脑中主要的谷氨酸转运蛋白 EAAT2。 EAAT2 在决定突触和突触外谷氨酸水平以及调节谷氨酸水平方面发挥着关键作用 生理性谷氨酸能神经传递，所有这些对于学习、记忆和突触健康都至关重要。 重要的是，EAAT2 活性在衰老和 AD 中均显着降低，并且与 后者的神经退行性变。该提案研究了 EAAT2 在衰老和 AD 中的病理生理学作用 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 衰老和 AD 小鼠模型中的概况，其次，通过 EAAT2 增强子的干预， 谷氨酸调节剂利鲁唑。此外，该提案使用了新开发的条件EAAT2敲除 (KO) 小鼠，用于进一步研究 EAAT2 对基因表达模式和行为的影响 老化的大脑。这些综合目标将描述 EAAT2 在衰老和 AD 大脑中的生物学作用 结构、分子和功能水平，并将测试 EAAT2 增强作为年龄- 相关的认知能力下降和AD。该提案建立在 PI 最近关于谷氨酸能失调的研究基础上 衰老和 AD 中脆弱的兴奋性突触、她出色的领导能力以及 导师在大脑结构分析（如电子显微镜）、神经生物学方面拥有丰富的经验 衰老、AD 和谷氨酸神经系统。申请人已经汇集了卓越且互补的 拥有相关专业知识的导师团队，包括 Bruce McEwen、John Morrison、Patrick Hof 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创新 最终可以识别和验证新目标的机制假设 开发针对与年龄相关的认知衰退和 AD 的有效治疗方法，但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 拥有实现成为独立和领导研究者的长期目标所需的工具 衰老和 AD 的转化神经科学研究。