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Mechanisms of mTOR-independent axon growth and guidance defects in TSC2 mutant human neurons

TSC2 突变人类神经元中 mTOR 独立轴突生长和引导缺陷的机制

基本信息

批准号：
10624773
负责人：
Timothy M Gomez
金额：
$ 35.29万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624773
关键词：
3-Dimensional Address Affect Animal Model Axon Binding Biological Assay Biological Models Brain imaging Cell Line Cell membrane Cells Cognitive deficits Complex Cues Cytoskeleton Data Defect Dendrites Development Disease Drug Screening Engineering Epilepsy Etiology FRAP1 gene Family Genetic Engineering Genomics Goals Growth Growth Cones Growth Factor Guanosine Triphosphate Phosphohydrolases Heterozygote Human In Vitro Intracellular Membranes Light Location Lysosomes Measures Mediating Mediator Metabolic Methods Modeling Molecular Mutation Nervous System Neurites Neurodevelopmental Disorder Neuroglia Neuronal Differentiation Neurons Pathway interactions Patients Phosphorylation Process Prosencephalon Protein Biosynthesis Regulation Research Role Seizures Series Signal Pathway Signal Transduction Site Symptoms Synapses TSC1 gene TSC2 gene Testing Therapeutic Therapeutic Intervention Time Tuberous Sclerosis United States National Institutes of Health Variant Work autism spectrum disorder autosome axon growth axon guidance axonal pathfinding cell behavior cortical tubers desensitization druggable target experimental study gain of function gene correction imaging study induced pluripotent stem cell loss of function mutant neural network neuron development neuronal growth novel overexpression protein complex response rho rho GTP-Binding Proteins subcellular targeting

项目摘要

Growing evidence suggests that patients with Tuberous Sclerosis Complex (TSC), like other neuro-developmental disorders, have mis-wiring of neuronal connections that form during development. These defects in neuronal connectivity likely contribute to symptoms of TSC, such as cognitive deficits, autism and epilepsy. However, defective axon guidance by human neurons has only been suggested from brain imaging studies, as models to study the molecular basis for mis-guidance of developing human neurons have not been developed. To directly address these fundamental questions, we will study the development of human neurons that we differentiate from human induced pluripotent stem cells (hiPSCs) from TSC patient-derived cells and their genetically engineered counterparts. Using a series of cell behavior and molecular signaling assays, we will compare TSC2 mutant neurons with their gene-corrected, isogenic control neurons both in vitro and within 3D forebrain spheroids. We will examine changes in mTORC1 and mTORC2 signaling pathways in TSC2 mutant neurons to determine the relative contributions of each signaling pathway to neuronal development. While modulation of mTOR-dependent protein synthesis has been suggested to be required downstream of both attractive and repulsive axon guidance in several animal model systems, it is unknown if similar mechanisms function in developing human neurons. Our surprising preliminary data suggest that TSC2 functions independent of mTOR in growth cones to directly regulate the cytoskeleton to control axon guidance. In this proposal, we will determine how loss of TSC2 function alters the development of human forebrain neurons, with a current focus on axon extension and sensitivity to key axon guidance cues, two important cellular consequences of abnormal TSC2 function. We will determine the molecular mechanisms downstream of TSC2 and test functionally how these signaling pathway contribute to abnormal axon extension and guidance cue responses. Over the long term, we believe our research may help identify key druggable targets in patients with TSC.

越来越多的证据表明，结节性硬化症（TSC）患者和其他神经发育障碍患者一样，在发育过程中形成的神经元连接出现了错误。这些