Kinase Dysfunction in Autism and Neurodevelopmental Disorders

自闭症和神经发育障碍中的激酶功能障碍

• 批准号: 10657059
• 负责人: Smita Yadav
• 金额: $ 72.22万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657059
• 关键词: Amino Acids; Binding; Biochemical; Biochemistry; Biological; Biological Assay; Biological Models; Biology; Catalytic Domain; Cell membrane; Cerebral cortex; DNA Sequence Alteration; Data; Development; Disease; Electrophysiology (science); Etiology; Functional disorder; Genes; Genetic Engineering; Growth; Hippocampus; Human; Human Engineering; In Vitro; Induced pluripotent stem cell derived neurons; Inherited; Investigation; Lead; Lipid Binding; Liposomes; Macrocephaly; Mediating; Membrane; Modeling; Molecular; Molecular Conformation; Molecular Structure; Morphology; Mutation; Neurodevelopmental Disorder; Neurons; Neuropathogenesis; Organoids; Pathogenesis; Pathway interactions; Phosphatidylinositols; Phospholipids; Phosphorylation; Phosphotransferases; Property; Protein Kinase; Protein Truncation; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Research Proposals; Role; Signal Pathway; Signal Transduction; Synapses; Testing; Vertebral column; X-Ray Crystallography; autism spectrum disorder; chemical genetics; comparative; excitatory neuron; experimental study; human disease; human stem cells; induced pluripotent stem cell; induced pluripotent stem cell technology; inhibitor; innovation; migration; mutant; nerve stem cell; neurogenesis; neuron development; neuronal growth; neuropathology; phosphoproteomics; reconstitution; stem cell model; stem cell technology; structural biology; three-dimensional modeling

ABSTRACT Kinase signaling exquisitely orchestrates each step of neuronal development, beginning at neurogenesis to neuronal integration into functional synaptic networks. Through their highly specific substrate phosphorylation, protein kinases regulate neuronal growth, activity and their plasticity. Despite the increasing evidence for a critical and causative role of kinase dysfunction in neurodevelopmental disorders (NDD), the mechanisms through which the human kinome controls neuronal development and how its dysfunction manifests in disease remain major gaps in the field of neurodevelopmental biology. In this proposal, we will investigate the role of protein kinase TAOK1, genetic mutations in which have been strongly associated with autism spectrum disorder, macrocephaly and neurodevelopmental delay. Based on our preliminary findings, the central hypothesis of this research proposal is that TAOK1 is a pleiotropic kinase that regulates neuronal development through its ability to directly bind phospholipids and remodel the neuronal membrane, and that dysfunction in TAOK1 signaling lead to neuropathogenesis. Our data show that (a) both de novo and inherited TAOK1 mutations in NDD induce aberrant neuronal membrane extensions that disrupt neuronal morphology and function and (b) TAOK1 can directly bind phosphoinositides enriched in the plasma membrane. Through integration of innovative approaches in proteomics, chemical-genetics, structural biology, stem cell technology and human disease relevant model systems, we seek to (Aim1) understand the mechanisms through which TAOK1 signaling mediates neuronal development, (Aim2) determine the biological principles that govern TAOK1 membrane binding and remodeling, and (Aim3) generate human stem cell derived neuronal models of TAOK1 associated disease in order to determine developmental perturbations as well as phosphoproteomic changes due to deficits in TAOK1 signaling. These studies will provide a comprehensive understanding of the role of a high confidence gene in the etiology of neurodevelopmental disorders.

抽象的 激酶信号从神经发生开始，精心编排神经元发育的每个步骤 神经元整合到功能突触网络中。通过其高度特异的底物磷酸化， 蛋白激酶调节神经元的生长，活性及其可塑性。尽管有越来越多的证据表明关键 激酶功能障碍在神经发育障碍（NDD）中的致病作用，该机制 人类动物组控制神经元的发育及其功能障碍在疾病中如何表现仍然主要 神经发育生物学领域的差距。在此提案中，我们将研究蛋白激酶的作用 TAOK1，与自闭症谱系障碍密切相关的遗传突变 和神经发育延迟。根据我们的初步发现，这项研究的中心假设 提议是TAOK1是一种多效激酶，它通过直接的能力来调节神经元发展 结合磷脂并重塑神经元膜，并在TAOK1信号中的功能障碍导致 神经病发生。我们的数据表明，（a）从头开始和遗传的taok1突变诱导异常 破坏神经元形态和功能的神经元膜扩展，（b）TAOK1可以直接结合 富含质膜的磷酸肌醇。通过整合创新方法 蛋白质组学，化学基因，结构生物学，干细胞技术和人类疾病相关模型 系统，我们寻求（AIM1）了解TAOK1信号介导神经元的机制 开发，（aiM2）确定控制陶克1膜结合和重塑的生物学原理， （AIM3）生成人类干细胞衍生的TAOK1相关疾病的神经元模型，以便 确定由于TAOK1缺陷而引起的发育扰动以及磷酸蛋白质组学的变化 信号。这些研究将对高信任基因在 神经发育障碍的病因。