[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.

项目摘要 衰老是海马神经发生的最重要的负调节剂，导致损害 突触可塑性和认知功能。该应用程序的主要目标是识别少年保护性 能够在老年小鼠中维持神经发生和认知功能的因素（JPF） 可以实现与年龄有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，表明有丝分裂检查点激酶BUBR1需要 在以后的生活中，保持适当的早期大脑发育和海马功能。具体来说，bubr1级是 在早期发展期间特别高，然后下降到成人水平，然后进一步下降 在自然老化过程中。鉴于神经发生在童年时期很健壮，但经历了进步的 随着衰老而下降，这种BUBR1的表达模式与年龄相关的神经发生下的下降相关。 但是，持续的BUBR1水平是否在老年大脑中具有保护作用，因此暗示了一种新颖的 在老年小鼠中保持适当的神经发生和相关海马功能的JPF仍然未知。 因此，本应用的主要目的是解决老年人是否持续的BUBR1持续较高 大脑可防止与年龄有关的海马功能障碍。为了支持这个想法，我们的初步数据证明了 BUBR1不足加速了海马神经发生中年龄依赖性损害。重要的是， 虽然高水平的BUBR1本身对年轻小鼠没有任何有害影响，但它会促进 老年小鼠的神经发生。基于这些发现，我们的中心假设是与 年龄有助于年龄依赖性的海马功能下降，并且持续较高的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。利用倍数 包括小鼠遗传学，共聚焦成像，电生理学和行为分析的方法，AIM 1将 在调节神经发生中，确定BUBR1的钥匙下游分子途径。鉴于 Wnt信号在神经发生和衰老中的确定作用，我们将探索Wnt的参与 BUBR1中神经发生的信号通路不足和老化小鼠。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是否改善了老年人的突触可塑性和认知功能 小鼠以神经发生依赖性方式。总而言之，我们的发现不仅会揭示年龄的病因 - 相关的认知障碍，但也提供了一个框架，治疗干预措施可能针对 神经源性在正常脑老化期间下降。考虑到与年龄相关的认知患病率 缺陷，确定改善海马功能的机械元素将具有重大影响 对于认知衰老，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