权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of Ankyrin-B in the Nervous System

锚蛋白-B 在神经系统中的作用

基本信息

批准号：
10548308
负责人：
Damaris N Lorenzo
金额：
$ 5.29万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2020-01-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10548308
关键词：
ANK2 gene ASD patient Adult Affect Anatomy Ankyrins Axon Axonal Transport Binding Biochemical Biological Assay Brain Brain Diseases Brain region Cell Adhesion Molecules Cell physiology Cells Complex Corpus Callosum Couples Cytoskeleton Data Defect Development Disease Etiology Failure Functional disorder Gene Delivery Glutamates Goals Grant Growth Human Image Impairment In Vitro Knock-out Knockout Mice Lead Length Maintenance Mediating Membrane Mental disorders Metabotropic Glutamate Receptors Microtubules Motor Mus Mutation Nervous system structure Neural Cell Adhesion Molecule L1 Neuraxis Neurodegenerative Disorders Neurodevelopmental Disability Neurologic Neurons Parkinson Disease Pathway Analysis Patients Phenotype Play Process Protein Isoforms Proteins Regulation Research Resolution Role Schizophrenia Semaphorin-3 Signal Transduction Somatosensory Cortex Spectrin Structure Synapses Synaptic Transmission Testing Variant Vertebral column Vesicle autism spectrum disorder axon growth axon guidance base cell motility de novo mutation density dynactin gene network in utero in vivo morphometry mouse model mutant nervous system disorder neuron development neuron loss neurotransmission novel postnatal period postsynaptic receptor synaptic function synaptic pruning synaptogenesis trafficking transmission process white matter

项目摘要

The establishment of functional neuronal networks in the developing and adult central nervous system (CNS) requires proper axonal specification, growth, branching, targeting, and synaptogenesis. Failure to appropriately interconnect brain regions during development or to refine those connections during maturation can lead to neurodevelopmental disabilities, such as autism, or to neurodegenerative and psychiatric disorders. De novo mutations in ANK2, which encodes ankyrin-B (AnkB), have been identified in autism spectrum disorder (ASD) patients, some of whom show aberrant axonal development. Neuronal loss of AnkB isoforms in mice results in absence of long axonal projections in the CNS and an overall reduction in axonal length, confirming that AnkB serves important roles in neuronal development in both humans and mice. AnkB has two major isoforms in the brain; ubiquitously expressed 220kDa (AnkB220) and neuron-specific 440kDa AnkB (AnkB440). We recently discovered that AnkB220 is motile and promotes microtubule-based axonal transport in cultured neurons to facilitate axonal growth. In contrast, AnkB440 interacts with cell adhesion molecules implicated in axon guidance and synaptogenesis. Neurons lacking AnkB440 have increased axon branching and synaptogenesis. We also found that AnkB is enriched at the postsynaptic density of glutamatergic synapses. The different phenotypes of the isoform-specific knockout in mice highlights the specialized functions of AnkB220 and AnkB440. Thus, there is a need to uncover the functional roles of neuronal AnkB and discern the cellular specialization of its AnkB220 and AnkB440 isoforms. Here, we will use novel mouse models lacking AnkB220 or AnkB440 in cortical neurons to unravel the precise cellular mechanisms underlying the neuronal development and connectivity deficits caused by the loss of these isoforms. Our research constitutes a novel effort to test our central hypothesis that AnkB coordinates neuronal structural and functional connectivity through the combined and specific roles of the AnkB220 and AnkB440 isoforms. To achieve our goals, we aim to: (1) Determine if AnkB220-driven axonal transport is required for the development and maintenance of long-range CNS axons in vivo; (2) Define molecular interactions required for AnkB440-mediated regulation of synaptic connections during brain development; and (3) Define the roles of AnkB in the postsynapse. Our studies will directly contribute to our understanding of the fundamental mechanisms of axonal growth and synaptogenesis, thereby informing the pathophysiology of ankyrin-related neurological and other brain disorders associated with deficits in white matter and synaptic connectivity.

发育中和成人中枢神经系统（CNS）功能神经元网络的建立