TSC-mTOR on neuron development

TSC-mTOR 对神经元发育的影响

基本信息

批准号：
9111074
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9111074
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 Electroporation Exhibits FRAP1 gene Filopodia Genes Genetic Goals Health Human Hyperactive behavior Hypertrophy IGFBP2 gene In Vitro Individual Lesion Letters LoxP-flanked allele Mediating Medical center Mendelian disorder Modeling Molecular Molecular Profiling Morphogenesis Multiple Hamartoma Syndrome Mus Mutation Neurons PTEN gene Pathway interactions Patients Prevention Prosencephalon Protein Kinase Publishing Ribosomal Protein S6 Kinase 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 in utero in vivo interest knock-down loss of function mutation mTOR Inhibitor malformation mouse model mutant neuron development new therapeutic target periventricular heterotopia prevent research study

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）：该提案将检验以下假设：直接MTOR效应子和下游以及MTOR独立的分子有助于结核性硬化症复合物（TSC）中皮质神经元肥大和错位。该提案的长期目标是预防或挽救TSC中的脑畸形和涉及PI3K途径的其他疾病。 TSC是由TSC1或TSC2突变引起的，导致MTOR多动和发育畸形与癫痫发作以及认知和精神缺陷的恶化。 MTOR抑制剂雷帕霉素是唯一的治疗选择，没有挽救所有缺陷，并且具有重大副作用，强调需要更好地了解TSC的分子基础并找到新的药物靶标。我们和其他人开发了与TSC相关皮质病变的小鼠模型。在这些模型中发现的一致缺陷是神经元的错位和树突肥大。脊柱缺陷尚不清楚。在这里，我们建议确定一些负责皮质金字塔神经元异常位置和形态发生（树突和刺）的分子参与者。 MTOR直接磷酸化转化抑制剂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。由TSC1/TSC2复合物抑制的规范MTOR激活剂Rheb可能独立于MTOR有助于某些缺陷，但这仍然是推测性的。在AIM 2中，我们建议确定哪些MTOR依赖性和非依赖性分子有助于TSC中的皮质缺陷。最后，在AIM 3中，我们将测试是否鉴定出鉴定的分子（例如FLNA）预防和挽救TSC中的神经元缺陷。我们将与野生型和转基因小鼠的Breunig博士合作，结合遗传和药理学操纵以及翻译核糖体亲和力纯化（TRAP）分析。