Molecular mechanisms that regulate p38 MAPK-dependent neuronal gene expression

调节 p38 MAPK 依赖性神经元基因表达的分子机制

基本信息

批准号：
9258109
负责人：
Lauren Bayer Horowitz
金额：
$ 4.4万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9258109
关键词：
Affect Anatomy Autistic Disorder Biological Models Brain Caenorhabditis elegans Calmodulin Cells Clinical Data Defect Dense Core Vesicle Development Developmental Biology Disease Epilepsy Exocytosis Functional disorder Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Genetic Genetic Models Genetic Transcription Homologous Gene Image Link Loss of Heterozygosity MAPK11 gene Measurement Measures Mediating Mental disorders Methods Mitogen-Activated Protein Kinases Molecular Monitor Morphology Mutate Mutation Nematoda Nervous System Physiology Nervous system structure Neuronal Differentiation Neurons Neurophysiology - biologic function Neurosciences Neurosecretion Phenotype Process Property Protein Secretion Reporter Role Schizophrenia Signal Pathway Signal Transduction Study models Testing Time Transcript Transgenes base cell type clinically relevant experimental study functional loss functional restoration in vivo mitogen-activated protein kinase p38 molecular marker mutant mutation screening nervous system disorder neural circuit neurodevelopment optogenetics programs promoter relating to nervous system transcriptome sequencing voltage

项目摘要

Project Summary. The nervous system comprises an extraordinary variety of neuronal cell types. A differentiated neuron type is defined by a unique gene expression pattern that determines its morphology, connectivity, and function. Deciphering developmental mechanisms that regulate neuronal gene expression is a major question in developmental biology and is crucial to understanding nervous system function. Better understanding of these mechanisms will also impact our understanding of neurological and psychiatric disorders associated with improper neural gene expression, such as autism and schizophrenia. The nematode C. elegans is an excellent model for the study of gene expression in the developing nervous system. The C. elegans nervous system comprises diverse neuron types that use conserved factors to regulate gene expression. Gene expression in many neuron-types can be monitored in vivo using fluorescent reporter transgenes, which allows the use of powerful genetic methods to discover factors required for neural gene expression. Such an approach identified the p38 MAP kinase (MAPK), PMK-3, as a factor required for proper gene expression and differentiation of a pair of C. elegans chemosensory neurons. We have found that mutations that block neurosecretion and neural excitability restore neural gene expression to p38 MAPK mutants, suggesting that neural activity antagonistically regulates p38 MAPK-dependent gene expression that promotes neurodifferentiation. This proposal will determine how neurosecretion and neural activity antagonize gene expression that defines a specific neuronal fate. Because activity-regulated gene expression is critical for the development and function of neural circuits, these studies will advance understanding of processes fundamental to brain function and whose dysfunction has been linked to neurological and psychiatric disorders.

项目摘要。神经系统包含种类繁多的神经元细胞类型。一个分化的神经元类型是由决定其形态的独特基因表达模式定义的，连接性和功能。破译调节神经元基因表达的发育机制是发育生物学中的一个主要问题，对于理解神经系统功能至关重要。更好的对这些机制的理解也将影响我们对神经学和精神病学的理解与神经基因表达不当相关的疾病，例如自闭症和精神分裂症。线虫线虫是研究神经系统发育中基因表达的优秀模型。 C. 线虫神经系统由多种神经元类型组成，它们使用保守因子来调节基因表达。可以使用荧光报告基因在体内监测许多神经元类型的基因表达转基因，允许使用强大的遗传方法来发现神经基因所需的因子表达。这种方法将 p38 MAP 激酶 (MAPK)、PMK-3 确定为正确表达所需的因子。一对秀丽隐杆线虫化学感应神经元的基因表达和分化。我们发现阻断神经分泌和神经兴奋性的突变恢复 p38 MAPK 的神经基因表达突变体，表明神经活动拮抗地调节 p38 MAPK 依赖性基因表达，促进神经分化。该提案将确定神经分泌和神经活动如何拮抗定义特定神经元命运的基因表达。因为活性调节的基因表达对于神经回路的发育和功能，这些研究将增进对过程的理解对大脑功能至关重要，其功能障碍与神经和精神疾病有关。