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TSC-mTOR on neuron development

TSC-mTOR 对神经元发育的影响

基本信息

批准号：
8653649
负责人：
Angelique Bordey
金额：
$ 36.42万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8653649
关键词：
Actin-Binding Protein Address Adverse effects Affect Affinity Chromatography Anterior Applications Grants Binding Proteins Cells Cognitive Collaborations Complex Cortical Malformation Data Defect Dendrites Dendritic Spines Dependence Development Disease Drug Targeting Electroporation Exhibits Filopodia Genes Genetic Goals Human Hyperactive behavior Hypertrophy IGFBP2 gene In Vitro Individual Lesion Letters Mediating Medical center Modeling Molecular Molecular Profiling Morphogenesis Multiple Hamartoma Syndrome Mus Mutation Neurons PTEN gene Pathway interactions Patients Prevention Prosencephalon Protein Kinase Publishing Ribosomes Role Seizures Sirolimus TSC1 gene TSC1/2 gene TSC2 gene Testing Therapeutic Time Transgenic Mice Translating Tuberous sclerosis protein complex Validation Vertebral column base brain malformation cell motility cingulate cortex filamin genome analysis hippocampal pyramidal neuron human FRAP1 protein in utero in vivo interest knock-down loss of function mutation mTOR Inhibitor malformation mouse model mutant neuron development novel periventricular heterotopia prevent public health relevance research study ribosomal protein S6 kinase 1

项目摘要

DESCRIPTION (provided by applicant): This proposal will test the hypothesis that the direct mTOR effectors and downstream as well as mTOR-independent molecules contribute to cortical neuron hypertrophy and misplacement in Tuberous Sclerosis Complex (TSC). The long term goal of this proposal is to prevent or rescue brain malformations in TSC and other disorders involving the PI3K pathway. TSC is caused by mutations in TSC1 or TSC2 leading to mTOR hyperactivity and developmental malformations associated with seizures and worsening of cognitive and psychiatric deficits. The mTOR inhibitor rapamycin is the only therapeutic option, does not rescue all defects, and has major side-effects emphasizing the need to better understand the molecular basis of TSC and find novel drug targets. We and others have developed mouse models of TSC-associated cortical lesions. Consistent defects found across these models are neuronal misplacement and dendrite hypertrophy. Spine defects remain unclear. Here, we propose to identify some of the molecular players responsible for abnormal placement and morphogenesis (dendrites and spines) of cortical pyramidal neurons. mTOR directly phosphorylates the translational repressor eIF4E binding protein (4E-BP) and p70 ribosomal S6 protein kinase 1 (S6K1). In Aim 1, we will determine whether 4E-BP and/or S6K1 mediate mTOR effects on cortical neuron development. The canonical mTOR activator, Rheb, which is inhibited by the TSC1/TSC2 complex may contribute to some defects independently of mTOR, but this remains speculative. In aim 2, we propose to identify which mTOR- dependent and -independent molecules contribute to cortical defects in TSC. Finally, in aim 3 we will test whether identified molecules (e.g. FLNA) prevent and rescue neuronal defects in TSC. We will use a combination of genetic and pharmacological manipulations as well as translating ribosome affinity purification (TRAP) analysis in collaboration with Dr. Breunig in wild-type and transgenic mice.

描述（由申请人提供）：本提案将验证mTOR直接效应物和下游以及mTOR独立分子参与结节性硬化症（TSC）皮质神经元肥大和错位的假设。本提案的长期目标是预防或挽救TSC和其他涉及PI3K通路的疾病的脑畸形。TSC是由TSC1或TSC2突变引起的，导致mTOR过度活跃和与癫痫发作以及认知和精神缺陷恶化相关的发育畸形。mTOR抑制剂雷帕霉素是唯一的治疗选择，并不能挽救所有的缺陷，并且有主要的副作用，这强调了更好地了解TSC的分子基础和寻找新的药物靶点的必要性。我们和其他人已经开发了tsc相关皮层病变的小鼠模型。在这些模型中发现的一致缺陷是神经元错位和树突肥大。脊柱缺损仍不清楚。在这里，我们提出确定一些分子参与者负责异常放置和形态发生（树突和棘）皮质锥体神经元。mTOR直接磷酸化翻译抑制因子eIF4E结合蛋白（4E-BP）和p70核糖体S6蛋白激酶1 （S6K1）。在Aim 1中，我们将确定4E-BP和/或S6K1是否介导mTOR对皮质神经元发育的影响。典型的mTOR激活剂Rheb被TSC1/TSC2复合物抑制，可能独立于mTOR导致一些缺陷，但这仍然是推测性的。在目的2中，我们提出确定哪些mTOR依赖和不依赖的分子有助于TSC的皮质缺陷。最后，在目标3中，我们将测试鉴定的分子（如FLNA）是否能预防和挽救TSC中的神经元缺陷。我们将与Breunig博士合作，在野生型和转基因小鼠中结合使用遗传和药理学操作以及翻译核糖体亲和纯化（TRAP）分析。