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.

项目摘要/摘要突触介导我们的神经系统中的神经传递。虽然设施或稳定突触连接促进信号传输，突触紧急情况对于在塑造大脑电路的过程中至关重要发展，但不了解。在自闭症谱系障碍（ASDS）中，突触消除受损已有观察到并暗示是ASD患者的认知部分定义的基础。很公认突触紧急情况需要基因转录的激活。但是，参与的转录因素和基本分子机制仍然难以捉摸。我们最近的工作表明了活动 - 通过肌细胞增强因子2（MEF2）消除依赖突触，需要去磷酸化泛素E3连接酶鼠双分钟2（MDM2）（Tsai等，2017）。我们的最新数据显示了 MDM2底物之一的肿瘤抑制p53的泛素化，以及p53活性的升高 MEF2激活。该观察结果表明p53介导的基因转录在活性 - 依赖突触消除。因为我们还观察到两只ASD小鼠的p53泛素化升高已知突触数量升高的模型，我们建议检验p53媒体的假设发育期间和神经元活性刺激的突触演变，并且绝对降低 p53活性导致ASDS中的突触数量升高。在AIM 1中，我们将确定p53在突触发展。在AIM 2中，我们将探索MEF2和P53之间的相互作用，以消除突触。 AIM 3我们将确定在两个ASD中的升高突触数中升高的p53泛素化的贡献鼠标模型。由于对癌症生物学领域中p53有广泛的了解，我们期望这一点迅速为神经遗传学和突触生物学研究的新途径的研究。此外，由于许多与p53相关的药物都是临床上可用的，因此我们的研究数据可以允许基础研究人员和临床医生在研究ASD和其他神经发育疾病的研究中取得快速增长。