Investigating the Mechanism of Optic Nerve Hypoplasia Associated with CASK Mutation

CASK 突变相关视神经发育不全的机制研究

基本信息

批准号：
9248362
负责人：
Konark Mukherjee
金额：
$ 40.25万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9248362
关键词：
Adhesions Affect Age Alleles Animal Disease Models Animal Genetics Animal Model Apoptosis Atrophic Autistic Disorder Axon Biological Birth Blindness Brain Cell Adhesion Molecules Cell Count Cells Childhood Cholera Toxin Clinical Complex Confocal Microscopy Congenital Disorders Congenital cerebellar hypoplasia DNA Sequence Alteration Data Defect Development Disease Electrons Estrogen Receptors Exhibits Female Future Genes Growth Heterozygote Hour Human Image Incidence Injection of therapeutic agent Knock-out Knockout Mice Label Lead Link Long-Term Effects LoxP-flanked allele Maintenance Modeling Molecular Morphology Mus Mutant Strains Mice Mutation Nature Neurons Optic Disk Disorder Optic Nerve Pathogenesis Pathologic Nystagmus Patients Pattern Phenotype Phosphotransferases Prevalence Publishing Retina Retinal Retinal Ganglion Cells Risk Factors Role Scaffolding Protein Secondary to Septo-Optic Dysplasia Septum Pellucidum Structure Synapses Tamoxifen Testing Therapeutic Thick Thinness Transgenes Visual Visual impairment Visual system structure X Chromosome X-Linked Mental Retardation astrogliosis autism spectrum disorder base cellular pathology discrete time falls imaging study membrane-associated guanylate kinase mouse model mutant novel offspring postnatal prenatal presynaptic public health relevance regenerative therapy retinal axon scaffold

项目摘要

DESCRIPTION (provided by applicant): Optic nerve hypoplasia (ONH) is one of the most common congenital optic disc disorders and is an increasingly prevalent cause of childhood blindness. In addition to being considered a pervasive developmental defect, an association between ONH and autism spectrum disorder (ASD) has been established. Despite its prevalence, the molecular and cellular mechanisms leading to ONH is not clear. ONH is most studied in the context of septo-optic dysplasia which is associated with absent septum pellucidum and midline defects. Here, we identified a novel mouse model of ONH and propose to use it to elucidate mechanisms that lead to phenotypes associated with the disease. Specifically, we discovered ONH in mice with reduced levels of CASK. Human mutations in CASK lead to X-linked mental retardation with some of the patients falling within ASD phenotype. Affected patients often present with ponto-cerebellar hypoplasia and optic nerve hypoplasia/atrophy. CASK is a specific kinase for synaptic adhesion molecule neurexin, mutations in neurexin and its trans-synaptic interacting partner neuroligin also are associated with ASD. Thus investigating CASK mutation as a model of ONH has the potential to provide molecular link between ASD and ONH. Our preliminary data indicate that CASK heterozygous knockout mice (+/-) exhibit a thinner optic nerve with axonal loss and signs of astrogliosis. We will use animal genetics, developmental and imaging studies to understand pathogenesis of ONH in these mice. Specifically we will analyze whether the axonal loss are primary or secondary in nature, the cell autonomous effect of CASK loss during and after development of optic nerve and the precise cellular pathology that is associated with ONH. Our proposal has the potential to uncover a molecular link between ASD and ONH.

描述（由申请人提供）：视神经发育不全（ONH）是最常见的先天性视盘疾病之一，并且是儿童失明的一个日益普遍的原因，除了被认为是一种普遍的发育缺陷之外，ONH 与自闭症谱系之间存在关联。尽管其普遍存在，但导致 ONH 的分子和细胞机制尚不清楚。在这里，我们发现了一种新的 ONH 小鼠模型，并建议用它来阐明导致与该疾病相关的表型的机制。具体来说，我们在 CASK 人类突变水平降低的小鼠中发现了 ONH。某些属于 ASD 表型的患者患有 X 连锁智力障碍，受影响的患者通常表现为脑桥小脑发育不全和视神经发育不全/萎缩。突触粘附分子神经毒素激酶、神经毒素及其跨突触相互作用伙伴神经连接蛋白的突变也与 ASD 相关，因此将 CASK 突变作为 ONH 模型进行研究有可能提供 ASD 和 ONH 之间的分子联系。 CASK 杂合基因敲除小鼠 (+/-) 表现出视神经变薄、轴突缺失和星形胶质细胞增生的迹象。我们将使用动物遗传学、发育和影像学研究来了解。我们将具体分析这些小鼠的轴突缺失是原发性还是继发性、视神经发育期间和之后的细胞自主效应以及与 ONH 相关的精确细胞病理学。揭示 ASD 和 ONH 之间分子联系的潜力。