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Exploring the role of p53 in synapse development and elimination

探索 p53 在突触发育和消除中的作用

基本信息

批准号：
10055071
负责人：
Nien-Pei Tsai
金额：
$ 39.76万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10055071
关键词：
Acute Age Apoptosis Biology Cancer Biology Cell Cycle Clinical Cognitive deficits Data Dendritic Spines Development Disease Double Minutes Electrophysiology (science)Equilibrium Excitatory Synapse FMR1 Fostering Gene Activation Genes Genetic Genetic Transcription Goals Hippocampus (Brain)Hypersensitivity Image Impairment Knock-out Knockout Mice Knowledge Link Mediating Mental Depression Molecular Mus Muscle Cells Nervous System Neoplasms Nervous system structure Neurons PTEN gene Pathway interactions Patients Pharmaceutical Preparations Pharmacology Prevention Protein Dephosphorylation Protein p53 Research Research Personnel Role Scaffolding Protein Seizures Sensory Signal Transduction Slice Social Interaction Structure Synapses Synaptic Transmission TP53 gene Tamoxifen Testing Ubiquitination Up-Regulation Work autism spectrum disorder brain shape conditional knockout enhancing factor insight knock-down mouse model myocyte-specific enhancer-binding factor 2 nervous system disorder neural circuit neurogenetics neurotransmission novel nutlin 3 postnatal protocadherin 10 research study small molecule inhibitor synaptogenesis therapeutic development tool transcription factor transmission process two-photon ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY/ABSTRACT Synapses mediate neurotransmission in our nervous systems. Although facilitation or stabilization of synaptic connections promotes signal transmission, synaptic elimination is vital to shaping the brain circuit during development, but is less understood. In autism spectrum disorders (ASDs), impaired synapse elimination has been observed and implicated to underlie parts of the cognitive deficits in ASD patients. It is well accepted that activation of gene transcription is required for synaptic elimination. However, the participating transcription factors and underlying molecular mechanisms remain elusive. Our recent work demonstrated that activity- dependent synapse elimination through myocyte enhanced factor 2 (MEF2) requires dephosphorylation of ubiquitin E3 ligase murine double minute-2 (Mdm2) (Tsai et al., 2017). Our latest data showed a reduction of ubiquitination of tumor suppressor p53, one of the Mdm2’s substrates, and an elevation of p53 activity upon MEF2 activation. This observation indicates a possible role of p53-mediated gene transcription in activity- dependent synapse elimination. Because we also observed elevated p53 ubiquitination in two ASD mouse models in which synapse number is known to be elevated, we propose to test a hypothesis that p53 mediates synapse elimination during development and upon neuronal activity stimulation, and that abnormally reduced p53 activity contributes to elevated synapse numbers in ASDs. In Aim 1 we will determine the role of p53 in synapse development. In Aim 2 we will explore the interplay between MEF2 and p53 in synapse elimination. In Aim 3 we will determine the contribution of elevated p53 ubiquitination in elevated synapse number in two ASD mouse models. Because of the extensive understanding of p53 within the field of cancer biology, we expect this research to quickly open a new avenue for the study of neurogenetics and synaptic biology. Furthermore, because many drugs related to p53 are clinically available, data from our research could allow basic researchers and clinicians to make rapid gains in the study of ASDs and other neurodevelopmental diseases.

项目总结/摘要突触介导我们神经系统中的神经传递。虽然促进或稳定突触连接促进信号传递，突触消除对于在大脑中形成脑回路至关重要。发展，但了解较少。在自闭症谱系障碍（ASD）中，受损的突触消除已经观察到并暗示了ASD患者认知缺陷的部分基础。人们普遍认为，突触消除需要基因转录的激活。然而，参与转录因素和潜在的分子机制仍然难以捉摸。我们最近的研究表明- 通过肌细胞增强因子2（MEF 2）的依赖性突触消除需要泛素E3连接酶鼠双微体-2（Mdm 2）（Tsai等人，2017年）。最新数据显示，肿瘤抑制因子p53（Mdm 2的底物之一）的泛素化，以及p53活性的升高， MEF 2激活。这一观察结果表明p53介导的基因转录在活性中的可能作用- 依赖性突触消除因为我们还观察到两个ASD小鼠中p53泛素化水平升高，模型中，突触数量是已知的是升高，我们建议测试一个假设，即p53介导在发育过程中和神经元活动刺激时突触消除， p53活性有助于ASD中突触数量的增加。在目标1中，我们将确定p53在突触发育在目标2中，我们将探讨MEF 2和p53在突触消除中的相互作用。在目的3：我们将确定p53泛素化在两种ASD中突触数量增加中的作用。小鼠模型。由于在癌症生物学领域中对p53的广泛理解，我们期望这一点。这项研究将为神经遗传学和突触生物学的研究迅速开辟一条新的途径。此外，委员会认为，由于许多与p53相关的药物在临床上是可用的，我们的研究数据可以让基础研究人员和临床医生在自闭症和其他神经发育疾病的研究中取得快速进展。