The Role of MDM2 in FMRP regulation of neuronal development

MDM2 在 FMRP 调节神经元发育中的作用

• 批准号: 10395504
• 负责人: Xinyu Zhao
• 金额: $ 40.4万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-09 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395504
• 关键词: Adolescent; Adult; Axon; Behavioral; Binding; Binding Proteins; Bioinformatics; Biological Models; Biometry; Brain; Brain region; Cells; Clinical Trials; Cognitive; Cognitive deficits; Complement; Computational Biology; Data; Development; Disease; Drug Targeting; Embryo; FMR1; Fragile X Syndrome; Genes; Genetic; Glutamates; Health; Heritability; Heterozygote; Hippocampus (Brain); Human; Impaired cognition; Impairment; Intellectual functioning disability; Investigation; Knockout Mice; Learning; Link; MDM2 gene; Malignant Neoplasms; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Messenger RNA; Morphogenesis; Mus; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Outcome; Outcome Study; Parahippocampal Gyrus; Pathway interactions; Pharmacology; Prefrontal Cortex; Process; Protein Deficiency; Proteins; Proteomics; RNA-Binding Proteins; Regulation; Research Personnel; Role; Testing; Translations; Ubiquitination; Vertebral column; Work; autism spectrum disorder; cancer therapy; cell type; cognitive function; dentate gyrus; developmental disease; dosage; drug candidate; drug repurposing; effective therapy; excitatory neuron; human stem cells; information processing; inhibitor; innovation; insight; mouse genetics; neural network; neurodevelopment; neurogenesis; neuron development; neurophysiology; neuropsychiatric disorder; newborn neuron; novel; novel therapeutics; nutlin 3; overexpression; postnatal; postnatal development; protein degradation; recruit; stem cells; synaptogenesis; therapeutic target; transcriptomics

Title: The Role of MDM2 in FMRP regulation of neuronal development Fragile X Mental Retardation Protein (FMRP) is an RNA binding protein that binds to specific mRNAs to control their stability, localization, and protein translation. Loss of FMRP leads to Fragile X syndrome (FXS), the most common heritable cause of intellectual disability, and is also the greatest single-gene contributor to autism. Despite extensive effort, the mechanisms underlying the learning deficits in FXS are not fully understood and an effective therapy for this devastating disorder is lacking. Disappointing results from recent clinical trials underscore the pressing need for innovation in both target selection and cell type consideration. The development of an appropriate neural network is a prerequisite for normal brain functions. Although most neurons in the mammalian brain are born during embryonic neurogenesis, a significant amount of neuronal development continues postnatally. Neuronal maturation, including dendritic and axonal morphogenesis, spine development, synaptogenesis/pruning, and circuit integration, is critical for proper brain function and human health. In addition, new glutamatergic neurons are continuously produced in the dentate gyrus (DG) of the hippocampus, one of a few brain regions, possibly the only region in humans, with lifelong neurogenesis. Postnatal neurogenesis is important for cognitive outcomes and its impairment is implicated in both neuropsychiatric disorders and neurodegenerative diseases. Our lab has pioneered the investigation of FMRP in postnatal neurogenesis and our work has provided a causal link between postnatal neurogenesis and cognitive function in FXS, a postnatal developmental disorder. Using postnatal neurogenesis as a model system, we recently discovered that FMRP controls the levels of active (phosphorylated- or P-) MDM2. We were able to use a low dosage of Nutlin-3, an MDM2 inhibitor in clinical trials as a cancer treatment, to rescue cognitive deficits of adult FXS mice. Elevated MDM2 activity is found in a number of disease conditions, mostly cancers, and has been a focus for drug targeting. However, how elevated MDM2 impacts neurodevelopment and neuropsychiatric disorders is unclear. Our preliminary data show that FMRP-deficiency neurons also have elevated MDM2 levels and MDM2 inhibition rescue neuronal dendritic deficits of these neurons. Our exciting results have presented us with a set of lingering questions that are central to our understanding of FMRP regulation of neuronal development and developing novel treatment for FXS. This proposal aims to test the hypothesis that MDM2 is a key mediator of FMRP regulation of neurodevelopment. We will determine whether genetic reduction of MDM2 during postnatal development rescue certain behavioral deficits of FMRP-deficient mice (Aim 1), determine whether MDM2 dysregulation contributes to developmental deficits of FMRP-deficient neurons (Aim 2), and identify proteins and pathways that mediate MDM2 inhibition rescue of FMRP deficiency (Aim 3). The outcome of this study will yield important new information leading to novel therapeutic applications for FXS and potentially other neurodevelopmental disorders as well.

标题：MDM2 在 FMRP 调节神经元发育中的作用 脆性 X 智力迟钝蛋白 (FMRP) 是一种 RNA 结合蛋白，可与特定 mRNA 结合以控制 它们的稳定性、定位和蛋白质翻译。 FMRP 缺失会导致脆性 X 综合征 (FXS)，这是最常见的 智力障碍的常见遗传原因，也是导致自闭症的最大单基因因素。 尽管付出了巨大的努力，FXS 学习缺陷背后的机制仍未被完全理解，并且 这种破坏性疾病缺乏有效的治疗方法。最近的临床试验结果令人失望 强调在靶点选择和细胞类型考虑方面迫切需要创新。这 适当的神经网络的发展是正常大脑功能的先决条件。虽然大多数 哺乳动物大脑中的神经元是在胚胎神经发生过程中诞生的，大量的神经元 出生后发育仍在继续。神经元成熟，包括树突和轴突形态发生、脊柱 发育、突触发生/修剪和电路整合对于正常的大脑功能和人类至关重要 健康。此外，新的谷氨酸能神经元在大脑的齿状回（DG）中不断产生。 海马体是少数几个大脑区域之一，可能是人类唯一具有终生神经发生的区域。 产后神经发生对于认知结果很重要，其损伤与认知结果有关 神经精神疾病和神经退行性疾病。我们实验室率先开展了 FMRP 的研究 在产后神经发生中，我们的工作提供了产后神经发生和认知之间的因果关系 FXS（一种产后发育障碍）中的功能。使用产后神经发生作为模型系统，我们 最近发现 FMRP 控制活性（磷酸化或 P-）MDM2 的水平。我们能够使用 低剂量的 Nutlin-3（一种 MDM2 抑制剂）正在临床试验中作为癌症治疗，以挽救认知缺陷 成年 FXS 小鼠。 MDM2 活性升高存在于多种疾病中，主要是癌症，并且 一直是药物靶向研究的重点。然而，MDM2 升高如何影响神经发育和神经精神 疾病尚不清楚。我们的初步数据表明，FMRP 缺陷神经元的 MDM2 水平也升高 MDM2 抑制可挽救这些神经元的神经元树突缺陷。我们令人兴奋的结果向我们展示了 一系列挥之不去的问题对于我们理解 FMRP 对神经元的调节至关重要 开发和开发 FXS 的新型治疗方法。该提案旨在检验 MDM2 是一个假设 FMRP 调节神经发育的关键介质。我们将确定 MDM2 的基因是否减少 在出生后发育期间挽救 FMRP 缺陷小鼠的某些行为缺陷（目标 1），确定 MDM2 失调是否会导致 FMRP 缺陷神经元的发育缺陷（目标 2），以及 鉴定介导 MDM2 抑制、拯救 FMRP 缺陷的蛋白质和途径（目标 3）。结果 这项研究将产生重要的新信息，从而为 FXS 带来新的治疗应用，并有可能 其他神经发育障碍也是如此。