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: 9920781
• 负责人: Xinyu Zhao
• 金额: $ 45.94万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920781
• 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; effective therapy; excitatory neuron; human stem cells; information processing; inhibitor/antagonist; 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智力低下蛋白(FMRP)是一种RNA结合蛋白，可与特定的mRNAs结合来控制 它们的稳定性、定位和蛋白质翻译。FMRP缺失导致脆性X综合征(FXS)，最常见的 智力残疾的常见可遗传原因，也是导致自闭症的最大单基因贡献者。 尽管进行了广泛的努力，但FXS学习缺陷的潜在机制尚未完全了解，而且 这种毁灭性的疾病缺乏有效的治疗方法。最近的临床试验结果令人失望 强调在目标选择和细胞类型考虑方面迫切需要创新。这个 开发合适的神经网络是正常大脑功能的先决条件。尽管大多数 哺乳动物大脑中的神经元是在胚胎神经发生期间出生的，这是相当数量的神经元 发育是后天继续的。神经元成熟，包括树突和轴突的形态发生，脊椎 发育、突触发生/修剪和电路整合对正常的大脑功能和人类是至关重要的。 健康。此外，新的谷氨酸能神经元在大鼠的齿状回(DG)不断产生。 海马体，为数不多的几个大脑区域之一，可能是人类唯一具有终生神经发生的区域。 出生后神经发生对认知结果很重要，其损害与这两种情况都有关 神经精神障碍和神经退行性疾病。我们实验室开创了FMRP研究的先河 在出生后神经发生和我们的工作提供了出生后神经发生和认知之间的因果联系 在FXS中的功能，一种出生后发育障碍。以出生后神经发生为模型系统，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 小剂量的Nutlin-3，一种临床试验中的MDM2抑制剂，作为癌症治疗，以挽救认知障碍 成年FXS小鼠。MDM2活性升高在许多疾病中被发现，主要是癌症，并具有 一直是毒品靶向的焦点。然而，MDM2升高如何影响神经发育和神经精神疾病 疾病尚不清楚。我们的初步数据显示，FMRP缺乏的神经元也有升高的MDM2水平 而抑制MDM2则可挽救这些神经元的树突缺失。我们令人兴奋的结果向我们展示了 提出了一系列挥之不去的问题，这些问题对于我们理解FMRP对神经元的调控至关重要 开发和开发FXS的新治疗方法。这一提议旨在检验MDM2是一种 FMRP调节神经发育的关键介质。我们将确定MDM2的遗传减少是否 在出生后发育过程中挽救FMRP缺陷小鼠的某些行为缺陷(目标1)，确定 MDM2失调是否导致FMRP缺陷神经元的发育缺陷(目标2)，以及 确定介导MDM2抑制和挽救FMRP缺陷的蛋白质和途径(目标3)。结果是 这项研究将产生重要的新信息，导致FXS的新治疗应用，并有可能 其他神经发育障碍也是如此。