Role of BubR1 as a juvenile protective factor in hippocampal aging

BubR1作为幼年保护因子在海马衰老中的作用

• 批准号: 9898040
• 负责人: Mi-Hyeon Jang
• 金额: $ 3.81万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898040
• 关键词: Adolescent; Adult; Affect; Age; Age-associated memory impairment; Aging; Anxiety; BUB1 gene; Behavior; Behavioral; Birth; Brain; Cells; Childhood; Clinical; Cognitive aging; Cognitive deficits; Data; Development; Disease; Electron Microscopy; Electrophysiology (science); Elements; Embryo; Etiology; Exhibits; Functional disorder; Generations; Genetic; Goals; Growth; Hippocampus (Brain); Human; Impaired cognition; Impairment; Intervention; Knowledge; Life; Mediating; Memory; Mental Depression; Mental Retardation; Microcephaly; Mitotic; Mitotic Checkpoint; Molecular; Molecular Target; Mus; Mutant Strains Mice; Mutation; Neuronal Plasticity; Neurons; Pathology; Pathway interactions; Pattern; Phosphotransferases; Play; Prevalence; Process; Public Health; Publishing; Regenerative Medicine; Regulation; Role; Synaptic plasticity; Testing; Therapeutic Intervention; Treatment Efficacy; WNT Signaling Pathway; Work; age related; age related cognitive disorder; age related neurodegeneration; aged; aging brain; aging hippocampus; base; brain size; cognitive disability; cognitive function; confocal imaging; design; improved; inhibitor/antagonist; insight; knock-down; nerve stem cell; neurogenesis; new therapeutic target; novel; overexpression; postnatal; postnatal development; prevent; protective factors; small hairpin RNA

PROJECT SUMMARY Aging is the most significant negative regulator of hippocampal neurogenesis, contributing to impairments in synaptic plasticity and cognitive function. The main goal of this application is to identify juvenile protective factors (JPFs) that are capable of maintaining neurogenesis and cognitive function in aged mice so that effective therapeutic strategies for age-related cognitive disorders can be realized. Towards identifying novel JPFs, we have recently provided first evidence that the mitotic checkpoint kinase BubR1 is required for maintaining proper early brain development and hippocampal function later in life. Specifically, BubR1 level is particularly high during early development and then declines to an adult level, followed by further decline during the natural aging process. Given that neurogenesis is robust in childhood, but undergoes a progressive decline with aging, such expression pattern of BubR1 correlates with age-dependent declines in neurogenesis. However, whether sustained BubR1 levels have a protective role in the aged brain, and thus suggest a novel JPF that maintains proper neurogenesis and related hippocampal function in aged mice, remains unknown. Therefore, the main objective of this application is to resolve whether sustained high level of BubR1 in aged brain prevents age-related hippocampal dysfunction. To support this idea, our preliminary data demonstrate that BubR1 insufficiency accelerates age-dependent impairments in hippocampal neurogenesis. Importantly, while a high level of BubR1 itself does not have any detrimental effects in young mice, it promotes neurogenesis in aged mice. Based on these findings, our central hypothesis is that reduced BubR1 levels with age contribute to age-dependent declines in hippocampal function, and that sustained high levels of BubR1 promote neurogenesis and improve synaptic plasticity and cognitive function in aged mice. Utilizing multiple approaches including mouse genetics, confocal imaging, electrophysiology, and behavior analysis, Aim 1 will determine a key downstream molecular pathway of BubR1 in regulating neurogenesis. Given the well- established role of Wnt signaling in neurogenesis and aging, we will explore the involvement of the Wnt signaling pathway in neurogenesis in both BubR1 insufficient and aged mice. Subsequently, Aim 2 will test whether a sustained high level of BubR1 can restore hippocampal neurogenesis in aged mice. Lastly, Aim 3 will determine if a sustained high level of BubR1 improves synaptic plasticity and cognitive function in aged mice in a neurogenesis-dependent manner. In summary, our findings will not only reveal the etiology of age- related cognitive disorders, but also provide a framework by which therapeutic interventions may target neurogenic declines during normal brain aging. Considering the prevalence of age-associated cognitive deficits, determining the mechanistic elements improving hippocampal function will hold significant implications for the fields of cognitive aging, neurogenesis, neural plasticity, regenerative medicine, and public health.

项目总结 衰老是海马神经发生的最重要的负调控因素，导致 突触可塑性和认知功能。这个应用程序的主要目标是识别青少年保护 能够维持衰老小鼠神经发生和认知功能的因子(JPF) 可以实现对年龄相关认知障碍的有效治疗策略。走向小说辨析 JPFS，我们最近提供了第一个证据表明有丝分裂检查点激酶BubR1是 在以后的生活中保持正常的早期大脑发育和海马体功能。具体来说，BubR1水平是 在发育早期特别高，然后下降到成年水平，然后进一步下降 在自然老化过程中。考虑到神经发生在童年时期是强健的，但经历了一个渐进的过程 随着年龄的增长而下降，BubR1的这种表达模式与神经发生的年龄相关性下降有关。 然而，持续的BubR1水平是否对衰老的大脑起到保护作用，从而提出了一种新的 JPF在老年小鼠中维持正常的神经发生和相关的海马区功能，目前尚不清楚。 因此，该应用的主要目的是解决老年人是否持续高水平的BubR1 大脑防止与年龄相关的海马体功能障碍。为了支持这一观点，我们的初步数据表明 BubR1不足加速了海马神经发生的年龄依赖性损伤。重要的是 虽然高水平的BubR1本身对幼鼠没有任何有害影响，但它促进了 老龄小鼠的神经发生。基于这些发现，我们的中心假设是，通过 年龄导致了海马区功能的年龄依赖性下降，并且持续高水平的BubR1 促进神经再生，改善衰老小鼠突触可塑性和认知功能。利用多个 包括小鼠遗传学、共聚焦成像、电生理学和行为分析在内的方法，目标1将 确定BubR1调控神经发生的关键下游分子通路。鉴于这口井- Wnt信号在神经发生和衰老中的作用已经确立，我们将探讨Wnt的参与 BubR1不足和衰老小鼠神经发生中的信号通路。随后，Aim 2将测试 持续高水平的BubR1能否恢复老龄小鼠的海马神经发生。最后，目标3 将确定持续高水平的BubR1是否能改善老年人的突触可塑性和认知功能 以神经发生依赖的方式感染小鼠。总而言之，我们的发现不仅将揭示年龄的病因- 相关的认知障碍，但也提供了一个框架，治疗干预可能有针对性的 在正常的大脑老化过程中，神经原性衰退。考虑到与年龄相关的认知的流行 缺陷，确定改善海马区功能的机制元素将具有重大意义 适用于认知老化、神经发生、神经可塑性、再生医学和公共卫生等领域。