The role of Foxp1-regulated signaling pathways in brain development and behavior

Foxp1调节的信号通路在大脑发育和行为中的作用

基本信息

批准号：
9273628
负责人：
Genevieve Konopka
金额：
$ 40.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9273628
关键词：
Acute Address Affect Alleles Autistic Disorder Automobile Driving Behavior Behavioral Brain Brain Diseases Brain region Cells Childhood Comorbidity Corpus striatum structure Data Data Set Development Developmental Delay Disorders Disease Electrophysiology (science)Embryo Etiology FMR1 FOXP1 gene Fragile X Syndrome Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Models Genetic Transcription Goals Heritability Hippocampus (Brain)Human Individual Injectable Intellectual functioning disability Knock-out Knockout Mice Knowledge Laboratories Molecular Mus Mutation Neurodevelopmental Disorder Neurons Pathway interactions Patients Play Regional Disease Regulator Genes Reporting Research Personnel Risk Risk Behaviors Rodent Rodent Model Role Signal Pathway Signal Transduction Slice Therapeutic Time Ultrasonics Viral autism spectrum disorder base cognitive function conditioned fear functional genomics insight loss of function mutation mind control nerve stem cell neuropsychiatric disorder novel therapeutic intervention postnatal programs public health relevance synaptic function targeted treatment transcription factor transcriptome transcriptome sequencing vocalization

项目摘要

DESCRIPTION (provided by applicant): Complete knowledge of the signaling pathways underlying brain development still remains unknown. The long- term goal of our laboratory is to elucidate the molecular signaling pathways disrupted in neurodevelopmental disorders that are important for brain development. Mutations in the gene encoding FOXP1 have previously been identified in individuals with developmental delay, intellectual disability, and autism. Our preliminary studies have shown that the transcription factor FOXP1 regulates genes important in brain development, and reduction in FOXP1 levels leads to behavioral changes in rodents. In addition, our data show that Foxp1 is a critical regulator of genes important for neuronal activity and loss of Foxp1 results in altered neuronal function. Based on these data, the central hypothesis driving this proposal is that FOXP1 is an orchestrator of transcriptional signaling cascades that are important for neuronal function and are at risk in neurodevelopmental disorders such as ASD. We propose to identify the developmental and regional disease-relevant targets of FOXP1 in the developing brain by using a combination of rodent models and human transcriptome data through three specific aims: 1) Identify the developmental transcriptional program regulated by Foxp1 in the brain; 2) Assess the role of Foxp1 and target genes in activity-dependent neuronal function; and 3) Determine the regional contribution of Foxp1 in the brain to specific ASD-relevant behaviors. Together, these aims will determine the transcriptional program regulated by Foxp1 throughout brain development and how Foxp1 gene regulation may be related to neuronal function and specific disease- relevant behaviors. Completion of the proposed aims will provide increased knowledge as to the molecular pathways that can be targeted for treatment in individuals with autism. The generated rodent models can be utilized to examine new therapeutic approaches for reversing autism-relevant behaviors. These data will also provide insight into the basic molecular mechanisms governing normal brain development.

描述（适用提供）：关于大脑发育潜在的信号通路的完整知识仍然未知。我们实验室的长期目标是阐明在对脑发育很重要的神经发育疾病中破坏的分子信号通路。编码FOXP1的基因中的突变先前已在发育延迟，智力残疾和自闭症的个体中鉴定出来。我们的初步研究表明，转录因子FOXP1调节基因在大脑发育中重要，而FOXP1水平的降低会导致啮齿动物的行为变化。此外，我们的数据表明，FOXP1是对神经元活动重要的基因的关键调节因子 FOXP1的丧失导致神经元功能改变。基于这些数据，推动该建议的中心假设是FOXP1是转录信号级联反应的编排，对神经元功能很重要，并且在ASD等神经发育障碍中有风险。我们建议通过使用啮齿动物模型和人类转录组数据的组合通过三个特定目的来确定发育大脑中FOXP1的发育和区域疾病与疾病相关的靶标：1）确定由FOXP1在大脑中调节的发育转录程序； 2）评估FOXP1和靶基因在活动依赖性神经元功能中的作用； 3）确定FOXP1在大脑中对特定ASD相关行为的区域贡献。总之，这些目标将确定在整个大脑发育过程中由FOXP1调节的转录程序，以及FOXP1基因调节如何与神经元功能和特定疾病相关的行为有关。拟议的目标的完成将提供更多关于可以针对自闭症患者治疗的分子途径的知识。生成的啮齿动物模型可用于检查新的治疗方法，以逆转自闭症与自闭症相关的行为。这些数据还将提供有关管理正常脑发育的基本分子机制的洞察力。