[Jang R01AG058560 transfer] Role of BubR1 as a juvenile protective factor in hippocampal aging

【Jang R01AG058560转】BubR1作为幼年保护因子在海马衰老中的作用

• 批准号: 10469911
• 负责人: Mi-Hyeon Jang
• 金额: $ 34.54万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469911
• 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; 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; insight; knock-down; mouse genetics; nerve stem cell; neurogenesis; new therapeutic target; novel; overexpression; postnatal; postnatal development; prevent; protective factors; small hairpin RNA; therapeutically effective

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.

项目概要 衰老是海马神经发生最重要的负调节因子，导致海马神经发生损伤 突触可塑性和认知功能。该应用程序的主要目标是识别青少年保护 能够维持老年小鼠神经发生和认知功能的因子（JPF） 可以实现与年龄相关的认知障碍的有效治疗策略。识别小说 JPFs，我们最近提供了第一个证据，证明有丝分裂检查点激酶 BubR1 是 维持适当的早期大脑发育和晚年海马功能。具体来说，BubR1水平为 在早期发育期间特别高，然后下降到成年水平，然后进一步下降 在自然老化过程中。鉴于神经发生在儿童时期是强大的，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依赖性下降相关。 然而，持续的 BubR1 水平是否对衰老的大脑具有保护作用，从而提出了一种新的方法 JPF 在老年小鼠中维持正常的神经发生和相关的海马功能仍然未知。 因此，本申请的主要目的是解决老年人体内BubR1是否持续高水平。 大脑可预防与年龄相关的海马功能障碍。为了支持这个想法，我们的初步数据表明 BubR1 不足会加速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 本身不会对幼鼠产生任何有害影响，但它会促进 老年小鼠的神经发生。基于这些发现，我们的中心假设是，降低 BubR1 水平 年龄导致海马功能的年龄依赖性下降，并维持高水平的 BubR1 促进神经发生并改善老年小鼠的突触可塑性和认知功能。利用多个 目标 1 将采用包括小鼠遗传学、共焦成像、电生理学和行为分析在内的方法 确定 BubR1 在调节神经发生中的关键下游分子途径。鉴于良好 Wnt 信号在神经发生和衰老中的作用已经确定，我们将探讨 Wnt 的参与 BubR1 不足和老年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 是否可以恢复老年小鼠的海马神经发生。最后，目标3 将确定持续高水平的 BubR1 是否可以改善老年人的突触可塑性和认知功能 小鼠以神经发生依赖的方式。总之，我们的研究结果不仅揭示了年龄的病因 相关的认知障碍，而且还提供了一个框架，通过该框架，治疗干预措施可以针对 正常大脑衰老过程中神经源性衰退。考虑到与年龄相关的认知能力的普遍存在 缺陷，确定改善海马功能的机制因素将具有重大意义 用于认知衰老、神经发生、神经可塑性、再生医学和公共卫生领域。

项目成果

Editorial: Adult neurogenesis as a regenerative strategy for brain repair.

• DOI: 10.3389/fnmol.2022.1041009
• 发表时间: 2022
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Berg, Daniel A.;Cho, Kyung-Ok;Jang, Mi-Hyeon
• 通讯作者: Jang, Mi-Hyeon

The selective cyclooxygenase-2 inhibitor NS398 ameliorates cisplatin-induced impairments in mitochondrial and cognitive function.

• DOI: 10.3389/fnmol.2023.1295991
• 发表时间: 2023
• 期刊: FRONTIERS IN MOLECULAR NEUROSCIENCE
• 影响因子: 4.8
• 作者: Rashid, Mohammad Abdur;Tang, Jason J.;Yoo, Ki-Hyun;Corujo-Ramirez, Ana;Oliveros, Alfredo;Kim, Sang Hoon;Ullah, Faheem;Altawell, Raad;Hawse, John R.;Cole, Peter D.;Jang, Mi-Hyeon
• 通讯作者: Jang, Mi-Hyeon

New Roles for Old Glue: Astrocyte Function in Synaptic Plasticity and Neurological Disorders.

• DOI: 10.5213/inj.1836214.107
• 发表时间: 2018-10
• 期刊: International neurourology journal
• 影响因子: 2.3
• 作者: Hussaini SMQ;Jang MH
• 通讯作者: Jang MH

Early stem cell aging in the mature brain.

• DOI: 10.1016/j.stem.2021.03.018
• 发表时间: 2021-05-06
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Ibrayeva A;Bay M;Pu E;Jörg DJ;Peng L;Jun H;Zhang N;Aaron D;Lin C;Resler G;Hidalgo A;Jang MH;Simons BD;Bonaguidi MA
• 通讯作者: Bonaguidi MA

Nicotinamide Mononucleotide Prevents Cisplatin-Induced Cognitive Impairments.

• DOI: 10.1158/0008-5472.can-20-3290
• 发表时间: 2021-07-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Yoo KH;Tang JJ;Rashid MA;Cho CH;Corujo-Ramirez A;Choi J;Bae MG;Brogren D;Hawse JR;Hou X;Weroha SJ;Oliveros A;Kirkeby LA;Baur JA;Jang MH
• 通讯作者: Jang MH