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Regulation of mTOR signaling in the developing cerebral cortex as a point of convergence for multiple autism risk factors

发育中大脑皮层中 mTOR 信号的调节作为多种自闭症危险因素的汇聚点

基本信息

批准号：
10573282
负责人：
Damon Theron Page
金额：
$ 46.25万
依托单位：
UNIVERSITY OF FLORIDA
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：
2016-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10573282
关键词：
Adult Area Behavior Behavioral Biological Biological Models Brain Cell Count Cerebral cortex Clinical Cognition Computer Analysis Data Data Set Development Exhibits FMR1 FRAP1 gene Funding Genetic Genetic Suppression Goals Golgi Apparatus Growth Heterozygote Human Immunohistochemistry Individual Insulin-Like Growth Factor I Intellectual functioning disability Intervention Label Laboratories Lead Link Macrocephaly Measures Medial Methyl-CpG-Binding Protein 2 Microcephaly Modeling Molecular Molecular Target Morphology Mutant Strains Mice Mutation NF1 gene Neuroanatomy Neurons Newborn Infant PTEN gene Pathway interactions Peripheral Pharmacological Treatment Phosphorylation Phosphotransferases Population Prefrontal Cortex Process Protein Biosynthesis Proteome Proteomics Regulation Reporting Research Risk Factors Signal Transduction Specificity Surveys Synapses TSC1 gene Testing Therapeutic Tissues Tyrosine Phosphorylation UBE3A gene Up-Regulation Western Blotting Work autism spectrum disorder behavioral phenotyping candidate identification cell cortex cell type design hippocampal pyramidal neuron individuals with autism spectrum disorder insight loss of function mTOR Signaling Pathway mouse model mutant neonatal mice neuronal cell body neuronal growth pharmacologic phosphoproteomics pleiotropism risk variant therapeutic candidate therapeutic target therapy development

项目摘要

PROJECT SUMMARY/ABSTRACT Signaling through mTOR is a critical regulator of protein synthesis in the developing brain, and numerous autism spectrum disorder (ASD) and intellectual disability (ID) risk genes have been identified that impinge on mTOR signaling and cause altered growth and connectivity at the level of brain areas/circuits or individual cell types. Mutations in dual-specificity tyrosine phosphorylation-regulated kinase 1a (DYRK1A) cause microcephaly and neuronal undergrowth in a subset of individuals with ASD and ID, as well as in mouse models. The mechanisms by which mutations in DYRK1A lead to microcephaly and ASD/ID are unknown but are critical to identify for the development of targeted treatments. Given the observations that multiple ASD risk genes that impact overall brain growth exhibit altered mTOR signaling and that decreased mTOR signaling in the developing cerebral cortex has been linked with microcephaly, pyramidal neuron undergrowth and deficits in behavior and cognition, we are testing the hypothesis that DYRK1A mutations cause microcephaly, neuronal undergrowth and ASD-relevant behavioral deficits through dysregulated mTOR signaling. Preliminary data collected during the previous funding period indicate that mTOR signaling is downregulated in the developing cerebral cortex of Dyrk1a mutant mice, and that upregulation of mTOR signaling via genetic suppression of Pten or pharmacological treatment with IGF-1 can rescue microcephaly and neuronal undergrowth in this model. The two aims of this proposal are designed to: 1) profile the effects of cerebral cortical Dyrk1a mutations on neuroanatomical and behavioral phenotypes relevant to the DYRK1A clinical population and to dysregulated mTOR signaling, and 2) test the hypothesis that Dyrk1a and mTOR signaling act in a common regulatory network to influence ASD-relevant brain growth and behavioral phenotypes. Completion of this project will elucidate molecular and cellular mechanisms of microcephaly, neuronal undergrowth and ASD-relevant behavioral deficits caused by mutations in DYRK1A and other ASD/ID risk genes that impinge on the mTOR pathway and will guide the development of treatments for the DYRK1A clinical population.

项目总结/摘要通过mTOR的信号传导是发育中的大脑中蛋白质合成的关键调节剂，自闭症谱系障碍（ASD）和智力残疾（ID）的风险基因已经被确定， mTOR信号传导，并在大脑区域/回路或单个细胞水平上引起生长和连接性的改变类型双特异性酪氨酸磷酸化调节激酶1a（DYRK 1A）突变导致在ASD和ID的个体子集中以及在小鼠中，模型DYRK 1A突变导致小头畸形和ASD/ID的机制尚不清楚，对于开发靶向治疗至关重要。考虑到多个ASD风险影响整个大脑生长的基因表现出mTOR信号的改变，而在大脑发育过程中mTOR信号的减少，发育中的大脑皮层与小头畸形、锥体神经元生长不足和缺陷有关。在行为和认知方面，我们正在测试DYRK 1A突变导致小头畸形的假设，神经元生长不足和ASD相关的行为缺陷通过失调mTOR信号。在前一个资助期收集的初步数据表明，mTOR信号转导下调， Dyrk 1a突变小鼠发育中的大脑皮层，以及通过遗传途径上调mTOR信号传导，抑制Pten或用IGF-1进行药物治疗可以挽救小头畸形和神经元畸形在这种模式下的灌木丛。该提案的两个目的是：1）描述大脑的影响，与DYRK 1A临床相关的神经解剖学和行为表型上的皮质Dyrk 1a突变群体和失调的mTOR信号，和2）测试的假设，Dyrk 1a和mTOR信号在共同的调节网络中起作用，以影响ASD相关的大脑生长和行为表型。本项目的完成将阐明小头畸形的分子和细胞机制，由DYRK 1A突变和其他ASD/ID风险引起的灌木丛和ASD相关行为缺陷影响mTOR通路并将指导DYRK 1A治疗的发展的基因临床人群。