Molecular mechanisms of spectrin-dependent axonal organization and function in cerebellar granule cells

小脑颗粒细胞血影蛋白依赖性轴突组织和功能的分子机制

• 批准号: 10605465
• 负责人: Reginald James Edwards
• 金额: $ 3.57万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605465
• 关键词: ANK2 gene; ANK3 gene; Ankyrins; Attention deficit hyperactivity disorder; Attentional deficit; Axon; Axonal Transport; Binding; Biochemical; Biological Assay; Brain; Cell Adhesion Molecules; Cerebellar Diseases; Cerebellum; Child; Colon; Complex; Cytoskeleton; Data Analyses; Dendrites; Development; Developmental Delay Disorders; Disease; Early Diagnosis; Electrophysiology (science); Epilepsy; Etiology; F-Actin; Fiber; Frequencies; Genetic; Glutamates; Hippocampus; Hyperactivity; Image Analysis; Individual; Intellectual functioning disability; Ion Channel; Lead; Macromolecular Complexes; Membrane; Membrane Lipids; Membrane Proteins; Membrane Transport Proteins; Microscopy; Molecular; Morphology; Motor; Mus; Neurodevelopmental Disorder; Neurologic; Neurologic Symptoms; Neurons; Organelles; Output; Patients; Play; Preparation; Proteins; Reporting; Research Project Grants; Resolution; Role; SCN2A protein; Sampling; Scientist; Seizures; Signal Transduction; Social Functioning; Sodium Channel; Spectrin; Structure; Synapses; Synaptic Transmission; Synaptic Vesicles; Syndrome; Techniques; Therapeutic Intervention; Training; Variant; Vesicle; autism spectrum disorder; cognitive function; comorbidity; design; granule cell; insight; live cell imaging; multiple omics; mutant; neuron component; neuronal excitability; neurotransmission; novel; superresolution microscopy; trafficking; training opportunity; vesicle transport; vesicular release; voltage

PROJECT SUMMARY βII-spectrin (encoded by SPTBN1), is a ubiquitous component of the submembrane neuronal cytoskeleton. βII- spectrin binds F-actin and ankyrins to organize complex networks of ion channels, membrane transporters and cell adhesion molecules. βII-spectrin also promotes bidirectional transport of organelles and vesicles. Our lab recently reported de novo SPTBN1 variants as the genetic cause of a developmental delay syndrome that is comorbid with intellectual disability, autism spectrum disorder, ADHD, and seizures. However, the neuron types and brain circuits most vulnerable to deficits in βII-spectrin function and their specific contribution to the diverse neurological presentations are not fully elucidated. My preliminary studies indicate that βII-spectrin plays important roles in modulating cerebellar function and that cerebellar dysfunction may contribute to the SPTBN1 syndrome. To begin to unravel the roles of βII-spectrin in the cerebellum, I will focus on investigating its function in cerebellar granule cells by determining how βII-spectrin promotes: 1) the organization of excitable axonal domains and 2) axonal organelle dynamics.

项目摘要 β II-血影蛋白（由SPTBN 1编码）是膜下神经元细胞骨架的普遍存在的组分。β Ⅱ- 血影蛋白结合F-肌动蛋白和锚蛋白，以组织离子通道、膜转运蛋白和 细胞粘附分子β II-血影蛋白还促进细胞器和囊泡的双向运输。我们实验室 最近报道，SPTBN 1的新生变异是一种发育迟缓综合征的遗传原因， 与智力残疾、自闭症谱系障碍、多动症和癫痫共病。然而，神经元类型 和脑回路最容易受到β II-血影蛋白功能缺陷的影响，以及它们对不同的 神经学表现尚未完全阐明。我的初步研究表明β II-血影蛋白 在调节小脑功能中起重要作用，小脑功能障碍可能导致SPTBN 1 综合征为了开始阐明β II-血影蛋白在小脑中的作用，我将重点研究其功能 通过确定β II-血影蛋白如何促进：1）可兴奋轴突的组织 结构域和2）轴突细胞器动力学。