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The Role of MDM2 in FMRP regulation of neuronal development

MDM2 在 FMRP 调节神经元发育中的作用

基本信息

批准号：
10612508
负责人：
Xinyu Zhao
金额：
$ 7.33万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/10612508
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

项目摘要

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：MDM 2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，它与特定的mRNA结合，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），这是智力残疾的常见遗传原因，也是自闭症的最大单基因贡献者。尽管进行了广泛的努力，但FXS中学习缺陷的潜在机制尚未完全了解，缺乏对这种破坏性疾病的有效治疗。最近的临床试验结果令人失望强调了在靶选择和细胞类型考虑方面创新的迫切需要。的发展适当的神经网络是正常大脑功能的先决条件。虽然大多数哺乳动物脑中的神经元在胚胎神经发生期间出生，发展在产后继续。神经元成熟，包括树突和轴突形态发生，棘发育、突触发生/修剪和电路整合对于适当的脑功能和人类健康至关重要。健康此外，在海马齿状回（DG）中不断产生新的多巴胺能神经元。海马体，少数几个大脑区域之一，可能是人类唯一的区域，具有终身神经发生。出生后的神经发生对认知结果很重要，其损伤与两者都有关系神经精神障碍和神经变性疾病。我们的实验室开创了FMRP的研究我们的工作提供了出生后神经发生和认知之间的因果关系 FXS是一种出生后发育障碍。使用出生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-）MDM 2的水平。我们能够使用低剂量的Nutlin-3，一种在临床试验中作为癌症治疗的MDM 2抑制剂，成年FXS小鼠MDM 2活性升高在许多疾病状况中发现，主要是癌症，成为药物靶向治疗的焦点。然而，MDM 2升高如何影响神经发育和神经精神疾病不清楚。我们的初步数据显示，FMRP缺陷神经元也具有升高的MDM 2水平， MDM 2抑制拯救了这些神经元的神经元树突缺陷。我们激动人心的成果向我们展示了一系列挥之不去的问题是我们理解神经元FMRP调节的核心，开发和开发FXS的新治疗方法。该提案旨在验证MDM 2是一种 FMRP调节神经发育的关键介质。我们将确定MDM 2基因的减少是否在出生后发育期间拯救FMRP缺陷小鼠的某些行为缺陷（目的1），确定 MDM 2失调是否有助于FMRP缺陷神经元的发育缺陷（目的2），以及鉴定介导MDM 2抑制拯救FMRP缺陷的蛋白质和途径（目的3）。成果这项研究将产生重要的新信息，导致FXS的新治疗应用，并可能其他的神经发育障碍。