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.

项目概要/摘要突触介导我们神经系统中的神经传递。突触连接促进信号传输，突触消除对于塑造大脑回路至关重要但在自闭症谱系障碍 (ASD) 中，突触消除受损却鲜为人知。人们普遍认为，自闭症谱系障碍 (ASD) 患者存在部分认知缺陷。突触消除需要基因转录的激活，但是参与转录。我们最近的工作表明，活性因素和潜在的分子机制仍然难以捉摸。通过肌细胞增强因子 2 (MEF2) 进行依赖性突触消除需要去磷酸化泛素 E3 连接酶鼠双分钟 2 (Mdm2)（Tsai 等人，2017）显示减少。肿瘤抑制因子 p53（Mdm2 的底物之一）泛素化，以及 p53 活性升高 MEF2 激活表明 p53 介导的基因转录在活性中可能发挥作用。因为我们还在两只 ASD 小鼠中观察到 p53 泛素化升高。在已知突触数量增加的模型中，我们建议检验 p53 介导的假设发育过程中和神经元活动刺激后的突触消除，并且异常减少 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 ASD 中的作用。在目标 2 中，我们将探讨 MEF2 和 p53 在突触消除中的相互作用。目标 3 我们将确定 p53 泛素化升高对两个自闭症谱系障碍 (ASD) 突触数量升高的贡献由于癌症生物学领域对 p53 的广泛了解，我们预计会出现这种情况。研究迅速为神经遗传学和突触生物学的研究开辟了一条新途径。由于许多与 p53 相关的药物已在临床上可用，因此我们研究的数据可以让基础研究人员并在自闭症谱系障碍和其他神经发育疾病的研究中取得快速进展。