TSC and sensory processing

TSC 和感官处理

基本信息

批准号：
9892431
负责人：
Angelique Bordey
金额：
$ 25.13万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892431
关键词：
Address Adult Affect Autophagocytosis Axon Biological Models Brain CRISPR/Cas technology Cells Child Cognitive deficits Cortical Dysplasia Data Defect Dendrites Dependence Development Disease Electroporation Embryo FRAP1 gene Goals Human Hyperactive behavior Individual Lateral Lead Length Life Link Mendelian disorder Molecular Molecular Abnormality Morphology Mus Mutation Neurodevelopmental Disorder Neurologic Deficit Neurons Pathway interactions Pattern Publishing Reporting Seizures Sensory Signal Transduction Sirolimus Somatic Mutation Somatosensory Cortex Synapses TSC1 gene TSC2 gene Testing Thalamic structure Time Translations Tuberous sclerosis protein complex Vibrissae Work autism spectrum disorder barrel cortex base brain abnormalities in utero information processing mTOR Signaling Pathway mTOR inhibition malformation migration mutant postnatal prevent response tool vector

项目摘要

The goal of this proposal is to identify how abnormalities of brain development in monogenic disorders involving the PI3K-mTOR pathway (e.g., tuberous sclerosis complex [TSC]) lead to alterations in circuit and in information processing. TSC is a classical disorder of the mTOR signaling pathway due to second-hit somatic mutations in TSC1 or TSC2 leading to mTOR hyperactivity and developmental malformations associated with seizures and neurological deficits. 50-60% of children with TSC have severe cognitive deficits and autism accompanied with abnormal sensory processing. Published work from our lab identified a combination of molecular and cellular alterations in murine neurons with hyperactive mTOR. These alterations include neuron misplacement and dysmorphogenesis that are conserved across cortical regions and between mice and humans. However, the impact of these defects on circuit formation and information processing, and the dependence on mTOR and downstream pathways at the circuit level remain unclear. Here, we propose to use the mouse barrel cortex as a well-established model system to start addressing the link between neuronal abnormalities and alterations in circuitry and sensory processing. Building from our previous findings, we hypothesize that dysmorphogenesis of layer (L) 4 barrel cortex neurons in TSC contributes to mTOR-dependent abnormalities in circuitry, functional connectivity, and sensory responses. We have the following two aims: (1) To test the hypothesis that mTOR hyperactivity in L4 neurons alters barrel circuitry and functional connectivity. (2) To test the hypothesis that reducing mTOR activity during a brief critical window and normalizing two downstream pathways prevent abnormalities in circuit and sensory responses in TSC condition. To address these aims, we will use in utero electroporation to express RhebCA and generate humanized Tsc1 mutations using CRISPR/Cas9 in L4 neurons of the barrel cortex.

该提案的目的是确定单基因中大脑发育异常涉及PI3K-MTOR途径的疾病（例如结节硬化症复合物[TSC]）导致电路和信息处理的改变。 TSC是MTOR的经典疾病由于TSC1或TSC2中的第二次撞击体突变引起的信号传导途径导致MTOR 与癫痫发作和神经系统相关的多动症和发育畸形缺陷。 50-60％的TSC儿童患有严重的认知缺陷，自闭症伴随着异常感觉处理。我们实验室的发表工作确定了分子的组合和多活跃MTOR的鼠神经元的细胞改变。这些更改包括神经元的错位和畸形发生，在皮质区域和在老鼠和人类之间。但是，这些缺陷对电路形成和信息处理以及对电路处MTOR和下游途径的依赖性水平尚不清楚。在这里，我们建议将鼠标桶皮层用作建立的良好模型系统开始解决神经元异常和改变之间的联系电路和感觉处理。从以前的发现中构建，我们假设 TSC中层（L）4桶皮质神经元的畸形生成有助于mTOR依赖性电路，功能连通性和感觉响应的异常。我们有以下两个目的：（1）检验以下假设：L4神经元中MTOR多动症改变桶电路和功能连接性。（2）检验以下假设，即在短暂时期降低MTOR活性关键窗口并标准化两个下游途径，以防止电路异常 TSC条件下的感觉响应。为了解决这些目标，我们将用于子宫电穿孔在L4神经元中使用CRISPR/Cas9表达Rhebca并生成人性化的TSC1突变枪管皮层的。