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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：
10397685
负责人：
Damon Theron Page
金额：
$ 29.04万
依托单位：
SCRIPPS 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 2022-04-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397685
关键词：
Adult Area Behavior Behavioral Biological Biological Models Brain Cell Count Cerebral cortex Cerebrum Clinical Cognition Computer Analysis Data Data Set Development Exhibits FMR1 FRAP1 gene Funding Genetic Genetic Suppression Goals Golgi Apparatus Growth 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 Neurons Newborn Infant PTEN gene Pathway interactions Peripheral Pharmacological Treatment Pharmacology 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 base behavioral phenotyping 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 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/文摘