PAX6-induced adult neurogenesis

PAX6诱导的成体神经发生

基本信息

批准号：
10614061
负责人：
Chun-Li Zhang
金额：
$ 48.05万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614061
关键词：
Adult Animals Astrocytes Axon Behavior Biological Process Brain CSPG4 gene Cell Transplantation Cell physiology Cells Central Nervous System ChIP-seq Cicatrix Clinical DNA Binding Domain Data Environment Genetic Goals Immune Injury Laboratories Mediating Modeling Molecular Motor Mus Nerve Degeneration Nerve Regeneration Nervous System Neuroglia Neurons Outcome Pathologic Patients Play Population Process Proliferating Rabies virus Recombinants Recovery of Function Research Role Series Signal Pathway Specific qualifier value Spinal Cord Spinal cord injury Stem Cell Factor Synapses Transcriptional Activation Domain Traumatic injury Vesicular stomatitis Indiana virus Work adult neurogenesis deep sequencing functional improvement genome-wide in vivo injury recovery mad itch virus migration mouse model nerve injury nerve stem cell neural circuit neural repair neurogenesis neuron loss neuronal excitability neuronal survival neurotrophic factor patch clamp postsynaptic presynaptic programs recombinant virus regenerative therapy repaired response single-cell RNA sequencing transcription factor tumorigenesis

项目摘要

Cell fate is controlled by master regulators, as is also the case in the nervous system. Pax6 is a highly conserved transcription factor consisting of two DNA-binding domains and a transcriptional activation domain. It is broadly expressed in neural stem/progenitor cells and plays pivotal roles in neuronal specification, migration, and axonal projections. Through a series of in vivo screens, we discovered that PAX6 is also capable of inducing new neurons from genetically traced glial cells in the adult mouse spinal cord. Based on such exciting data, we hypothesize that PAX6-induced adult neurogenesis from resident glial cells may represent an alternative strategy for neural regeneration. The major goal of this project is to characterize the PAX6-induced adult neurogenesis process and determine its functional role following traumatic neural injuries. We propose three specific aims to accomplish this goal. First, we will employ genetic lineage tracing and genome-wide deep sequencing to understand how PAX6 induces new neurons from resident glial cells in the adult mouse spinal cord. Secondly, we will employ recombinant virus-mediated transsynaptic tracing to delineate the network connections of PAX6- induced new neurons. And thirdly, we will use chemogenetics to tease out the functional role of PAX6-induced new neurons on behavior in adult mice with traumatic injury.

细胞命运由主调节器控制，而神经系统也是如此。 PAX6是高度保守的转录因子由两个DNA结合域和一个转录激活结构域组成。它是广义的在神经茎/祖细胞中表达，并在神经元规范，迁移和轴突中扮演关键作用预测。通过一系列体内屏幕，我们发现PAX6也能够诱导新的来自成年小鼠脊髓中基因追踪神经胶质细胞的神经元。基于这样令人兴奋的数据，我们假设PAX6诱导的居民神经胶质细胞的成年神经发生可能代表了另一种策略用于神经再生。该项目的主要目的是表征PAX6诱导的成年神经发生工艺并确定创伤性神经损伤后其功能作用。我们提出了三个具体目标实现这一目标。首先，我们将采用遗传谱系跟踪和全基因组深度测序了解PAX6如何诱导成年小鼠脊髓中常驻神经胶质细胞的新神经元。第二，我们将采用重组病毒介导的透射性跟踪来描述PAX6-的网络连接诱导新神经元。第三，我们将使用化学遗传学来阐明PAX6诱导的功能作用创伤性损伤成年小鼠行为的新神经元。