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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/文摘