Linking metabolism, neural function, and aging

将新陈代谢、神经功能和衰老联系起来

• 批准号: 10594465
• 负责人: Kaveh Ashrafi
• 金额: $ 50.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594465
• 关键词: 5' -AMP-activated protein kinase; Adult; Affect; Age; Age of Onset; Aging; Amino Acid Transporter; Animals; Association Learning; Autophagocytosis; Behavioral Assay; Biochemical; Biochemical Pathway; Biological Assay; CREB1 gene; Caenorhabditis elegans; Cell physiology; Cells; Characteristics; Cognition; Complement; Complex; Data; Defect; Development; Disease; Distant; Enzymes; FRAP1 gene; Funding; Gene Expression; Genes; Glutamates; Goals; Image; Impaired cognition; Insulin; Investigation; Kynurenic Acid; Kynurenine; Learning; Link; Longevity; Mammals; Measurement; Measures; Memory; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Molecular Genetics; Movement; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurodegenerative Disorders; Neuromodulator; Neuronal Plasticity; Neurons; Neurophysiology - biologic function; Organelles; Organism; Pathway interactions; Pattern; Play; Process; Production; Proteins; RNA-Binding Proteins; Regulation; Reporter; Risk Factors; Role; Signal Pathway; Signal Transduction; Site; Stress; System; Therapeutic; Tissues; Transcriptional Regulation; Tryptophan; Variant; active control; age effect; age related; antagonist; cognitive function; dietary restriction; enzyme pathway; experimental study; forgetting; long term memory; memory acquisition; mimetics; mutant; neural; neural correlate; neuroimaging; neuromechanism; neuroregulation; protein folding; receptor; tau Proteins; transcription factor

PROJECT SUMMARY/ABSTRACT A general characteristic of aging is diminution of cognitive functions. Aging is also one of the greatest risk factors for the development of neurodegenerative disorders. Dietary restriction, DR, and molecular mechanisms that mimic aspects of it, DR mimetics, are under intense investigation as they delay some of the cognitive declines of aging and neurodegenerative disorders. These perturbations generally extend lifespan in several species. In C. elegans, we have discovered that DR and some DR mimetics also enhance a simple form of learning, whose molecular underpinnings are involved in learning in mammals. We have discovered that changes in a single, neuromodulatory metabolite, kynurenic acid (KYNA), account for the beneficial effects of DR and multiple DR mimetics on learning in C. elegans. We have identified the specific neural sites of KYNA production as well as N-methyl D-aspartate receptor (NMDAR)-expressing neurons whose activity is regulated by KYNA in the context of learning. These findings are consistent with KYNA serving as an NMDAR antagonist. Additionally, we have discovered that a significant portion of age-onset decline in learning is due to age-dependent accumulation of KYNA. We have also found evidence that learning defects caused by a disease variant of tau, a protein associated with neurodegeneration, may be, in part, due to unanticipated increases in KYNA. Significantly, despite being intertwined with aging, changing KYNA levels does not affect lifespan. Thus, we have pinpointed a direct link between a variety of metabolic and stress perturbations and mechanism of neural plasticity. KYNA has desirable attributes as a potential therapeutic strategy as reducing KYNA levels, even when initiated in adults, blunts learning declines in worms. Existing data support the notion that KYNA affects mammalian cognition and that KYNA accumulates with age. Our goal here is to understand the factors that regulate KYNA accumulation, especially during aging. A particular challenge in both C. elegans and mammals is that despite ubiquitous availability of tryptophan, neural KYNA can be produced in highly localized spaces yet be influenced by distant tissues through effects on substrate availability. To achieve our goals, we will combine behavioral assays with molecular genetic, neural imaging, and direct biochemical metabolite measurements to investigate the intersection of aging, stress, and metabolic pathways with KYNA-dependent learning. We will investigate a candidate transporter that may play a regulatory role through its transport of the substrate needed to make KYNA. We will explore the provocative hypothesis that protein folding stress affects flux through the kynurenine pathway cell non-autonomously with detrimental effects on learning. Finally, we will investigate the molecular relationship of KYNA to conserved mechanisms of memory acquisition as well as newly discovered mechanisms that actively promote forgetting.

项目总结/摘要 衰老的一个普遍特征是认知功能减退。衰老也是最大的风险之一 神经退行性疾病发展的因素。饮食限制、DR和分子 模拟它的某些方面的机制，DR模拟物，正在进行深入的研究，因为它们延迟了一些 认知能力下降和神经退行性疾病。这些扰动通常会延长 几个物种。In C.我们已经发现DR和一些DR模拟物也增强了一种简单的形式， 它的分子基础与哺乳动物的学习有关。我们发现 单一神经调节代谢物犬尿烯酸（KYNA）的变化解释了 DR和多个DR模拟器在C中的学习。优美的我们已经确定了KYNA的特定神经部位 以及表达N-甲基D-天冬氨酸受体（NMDAR）的神经元，其活性受到调节 通过KYNA在学习的背景下。这些发现与KYNA作为NMDAR一致 拮抗剂此外，我们还发现，年龄增长导致的学习能力下降很大一部分是由于 KYNA的年龄依赖性积累。我们还发现了由疾病引起的学习缺陷的证据 tau蛋白是一种与神经退行性变相关的蛋白质，其变异可能部分是由于tau蛋白的意外增加。 凯娜值得注意的是，尽管与衰老交织在一起，但KYNA水平的变化不会影响寿命。 因此，我们已经确定了各种代谢和应激扰动与机制之间的直接联系 神经可塑性。KYNA具有作为潜在治疗策略的理想属性，如降低KYNA水平， 即使在成年人中开始，也会减缓蠕虫的学习能力下降。现有数据支持KYNA 影响哺乳动物的认知，KYNA随着年龄的增长而积累。 我们的目标是了解调节KYNA积累的因素，特别是在衰老过程中。一 在C.尽管色氨酸无处不在， 神经KYNA可以在高度局部化的空间中产生，但通过影响 底物可用性为了实现我们的目标，我们将联合收割机结合分子遗传学，神经 成像和直接的生化代谢物测量，以调查衰老，压力和 代谢途径与KYNA依赖性学习。我们将调查一个候选运输机， 通过运输制造KYNA所需的底物发挥调节作用。我们将探讨挑衅性的 假设蛋白质折叠应激影响通过犬尿氨酸途径细胞的通量， 对学习的不利影响。最后，我们将研究KYNA与保守的 记忆获得的机制以及新发现的积极促进遗忘的机制。