Differential Brain-Region Specific Roles of CASK in Optic Nerve Hypoplasia and Pontocerebellar Hypoplasia

CASK 在视神经发育不全和脑桥小脑发育不全中的不同脑区特异性作用

基本信息

批准号：
10427180
负责人：
Paras Patel
金额：
$ 1.55万
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：
2021
资助国家：
美国
起止时间：
2021-04-13 至 2022-05-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10427180
关键词：
ARHGEF5 gene Acute Adult Affect Anatomy Apoptosis Apoptotic Ataxia Atrophic Brain Brain region Caliber Cell Adhesion Molecules Cell Count Cell Death Cell physiology Cells Cellular Stress Cerebellar degeneration Cerebellum Cessation of life Chronic Congenital cerebellar hypoplasia DNA Nucleotidylexotransferase DNA Sequence Alteration Data Deterioration Development Dorsal Electrons Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Evoked Potentials Fibrous Astrocyte Frequencies Functional disorder Gene Mutation Genes Genetic Genetic Diseases Glial Fibrillary Acidic Protein Human Image Impairment In Situ Hybridization In Situ Nick-End Labeling Individual Injections Iron Knockout Mice Label Lateral Geniculate Body Lead Link Lipid Peroxidation Lipids Longevity Maintenance Measures Mediating Microcephaly Microscopy Modeling Molecular Morphology Mosaicism Motor Mus Mutation Nature Necrosis Nerve Degeneration Nervous System Physiology Neuraxis Neurology Optic Nerve Oxidative Stress Pathogenicity Pathologic Pathology Pathway interactions Personal Satisfaction Phenotype Photons Physiological Physiology Play Pontine structure Pontocerebellar hypoplasia Productivity Property Proteins Public Health Purkinje Cells RIPK3 gene Reactive Oxygen Species Retina Retinal Ganglion Cells Role Scaffolding Protein Slice Specificity Stains Stress Synapses System Tamoxifen Testing Thalamic structure Thinness Time Tomatoes United States Vision Visual Visual Cortex Visual evoked cortical potential Visual system structure X Inactivation awake base brain volume cell type functional loss granule cell mouse model nervous system development nervous system disorder neurophysiology oxidation postnatal promoter protein complex ranpirnase translational neuroscience

项目摘要

PROJECT SUMMARY Understanding how different regions of the central nervous system (CNS) are affected by genetic insults is critical to advancing the study of CNS pathologies which present a major public health burden in the United States. The cerebellum and optic nerve are two such regions that are disproportionately hypoplastic in the majority of cases of CASK gene mutation in humans. CASK is an enigmatic multi-domain scaffolding protein which plays a vital role in organizing protein complexes at the pre-synapse through interactions with both active zone proteins and trans-synaptic adhesion molecules such as liprins-α and neurexins. Mutations in the X-linked CASK gene in humans are largely post-natally lethal in the hemizygous condition and result in microcephaly with pontine and cerebellar hypoplasia (PCH) as well as optic nerve hypoplasia (ONH) in heterozygous mutations. While CASK has been traditionally regarded as playing a role in CNS development, recent data indicate that it plays a continued role in the maintenance of the adult CNS. Specifically, acute global deletion of Cask in adult mice using a CreER-Tamoxifen system leads to progressive degeneration in motor coordination culminating in profound ataxia several months after tamoxifen injection. This coincides with a progressive deterioration of cerebellar gross morphology. Thus, this presents a unique opportunity to understand the continued role of a gene, previously regarded as developmentally important, in the function of the adult CNS and how this function may differ in a region-specific manner. Recently, it has been demonstrated that progression of ONH in the context of CASK-loss is non-cell autonomous in nature as deleting Cask from retinal ganglion cells themselves does not exacerbate ONH, but deleting it from fibrous astrocytes of the optic nerve does exacerbate ONH. However, when Cask is deleted specifically in granule cells (GCs) using a Calb2 promoter driven Cre recombinase, there appears to be a cell- autonomous death of GCs. This provides an opportunity to examine how underlying etiopathology and functional loss differ in two regions given the same genetic insult. As granule cells are the major excitatory driver of the cerebellum, this project will investigate the progression of granule cell loss, the correlation of granule cell loss to functional motor loss and ataxia, and the electrophysiological implications of loss of the major excitatory driver in an isolated brain region. Further, the project will elucidate whether aberrations in spike-timing and frequency among cerebellar Purkinje cells precede or follow anatomical reductions in granule cell number. The project will also examine whether visual function correlates to optic nerve diameter in models which display ONH but not PCH and vice versa using visual evoked potential recordings from V1 of visual cortex and the dorsal lateral geniculate nucleus of the thalamus. Finally, the study will determine molecular mechanisms of non-apoptotic or apoptotic cell death underlying loss of GCs. Thus, the study will investigate differing causes and functional consequences with region-specificity in the context of a single genetic insult using Cask deletion as a test-case.

项目摘要了解中枢神经系统（CNS）的不同区域受到遗传损伤的影响至关重要促进对CNS病理学的研究，该病理在美国呈现了一个主要的公共卫生伯恩。小脑和视神经是两个这样的区域，在大多数情况下，它们不成比例不足人类桶基因突变的。木桶是一种神秘的多域脚手架蛋白，起着重要的作用通过与活性区蛋白质相互作用和反式突触粘合剂分子，例如脂肪 - α和神经毒素。 X连锁木桶基因中的突变人类在半合理状态下主要是在后期致命的，并导致蓬蒂恩和小脑发育不全（PCH）以及杂合突变中的视神经发育不全（ONH）。虽然传统上被认为CASK在CNS开发中起着作用，但最近的数据表明它在维持成人中枢神经系统中起着持续的作用。具体而言，急性全球删除桶装使用CRER-TAMOXIFEN系统的成年小鼠导致运动协调性逐渐变性罗昔着这昔佛剂注射几个月后，在深刻的共济失调中达到高潮。这与进步的小脑总形态的恶化。这是一个独特的机会来了解一个基因的持续作用，以前被认为在成人中枢神经系统的功能中被认为是重要的重要作用该函数如何以特定区域的方式有所不同。最近，已经证明，在桶式流浪的背景下，ONH的进展是非细胞的自然本质上的自主是从视网膜神经节细胞中删除桶子本身不会加剧，而是会加剧从视神经的纤维星形胶质细胞中删除它会加剧。但是，当木桶被删除时特别是使用CalB2启动子驱动的CRE重组酶在颗粒细胞（GCS）中，似乎有一个细胞 GCS的自主死亡。这提供了一个机会来检查基本病理学和功能鉴于相同的遗传损伤，两个区域的损失差异。因为颗粒细胞是主要令人兴奋的驱动力小脑，该项目将研究颗粒细胞损失的进展，颗粒细胞损失与功能性运动损失和共济失调，以及主要兴奋驱动器丧失的电生理学意义在孤立的大脑区域。此外，该项目将阐明尖峰和频率的畸变是否存在在小脑Purkinje细胞中，或遵循颗粒细胞数的解剖学减少。该项目将还要检查视觉功能是否与显示ONH但不显示的模型中的视神经直径相关 PCH和VICE VESA使用视觉诱发的潜在录音，来自Visual Cortex和背侧侧面的V1 丘脑的基因核。最后，该研究将确定非凋亡或 GCS的凋亡细胞死亡损失。这是研究将研究分化原因和功能在单个遗传侮辱的背景下，使用木桶缺失作为测试案例的后果。