Oligodendroglial isoforms of ANK3 and their role in CNS function

ANK3 的少突胶质细胞亚型及其在中枢神经系统功能中的作用

基本信息

批准号：
10064013
负责人：
MATTHEW N RASBAND
金额：
$ 40万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064013
关键词：
ANK3 gene Adolescence Adult Affect Age-Months Amino Acids Axon Behavior Bioinformatics Biological Bipolar Disorder Brain Cell Adhesion Molecules Code Complex Defect Development Diagnosis Disease Etiology Exons Functional disorder Gene Expression Genes Genetic Genotype Heritability Intercellular Junctions Knockout Mice Lead Link Lipids Location Modeling Modification Molecular Moods Mus Myelin Neural Conduction Neurons Oligodendroglia Pathogenesis Physiology Play Potassium Channel Protein Isoforms RNA Splicing Ranvier&apos s Nodes Reporting Reproducibility Risk Role Scaffolding Protein Schizophrenia Signal Transduction Site Structure Symptoms Time Transcript Treatment Efficacy United States Variant autism spectrum disorder conditional knockout gain of function genome wide association study hypomania insight loss of function mouse model neurofascin neuropsychiatric disorder novel oligodendrocyte myelination overexpression white matter

项目摘要

New Abstract: The causes of complex neuropsychiatric disorders including schizophrenia, bipolar disorder, and autism remain poorly understood. Importantly, many neuropsychiatric disorders are highly heritable, indicating the underlying cause is genetic rather than environmental. Large genome-wide association studies (GWAS) have begun to reveal specific genes associated with these disorders. Among these, ANK3 (the gene coding for AnkyrinG (AnkG)) is potentially associated with bipolar disorder, schizophrenia, and autism. However, how ANK3 variants contribute to these disorders remains unknown. Importantly a loss-of-function ANK3 splice variant containing a novel exon (termed BDex) found only in oligodendrocytes may be protective against bipolar disease. We previously found AnkG in paranodes of myelinating oligodendrocytes, where it functions in the timely assembly of paranodal junctions during early development. However, the function of oligodendroglial AnkG in older mice remains unknown. We will determine the function of AnkG in oligodendrocytes, and more specifically the function of BDex. We will define the precise location of BDex-containing AnkG in oligodendrocytes. We will use loss-of-function and gain-of-function mouse models to investigate the role of oligodendroglial ANK3 variants in the brain. We will examine node and paranode structure, myelin, myelinated axon physiology, and behavior. Together, these studies will begin to uncover the role of oligodendroglial AnkG and BDex AnkG, and may reveal insights into the molecular pathophysiology of ANK3-associated neuropsychiatric disorders.

新摘要：包括精神分裂症、双相情感障碍和自闭症在内的复杂神经精神疾病的病因仍知之甚少。重要的是，许多神经精神疾病具有高度遗传性，这表明根本原因是遗传而非环境。大型全基因组关联研究（GWAS）已开始揭示与这些疾病相关的特定基因。其中，ANK3（编码 AnkyrinG (AnkG) 的基因）可能与双相情感障碍、精神分裂症和自闭症相关。然而，ANK3 变异如何导致这些疾病仍不清楚。重要的是，仅在少突胶质细胞中发现的含有新外显子（称为 BDex）的功能丧失 ANK3 剪接变体可能可以预防双相情感障碍。我们之前在髓鞘化少突胶质细胞的节旁发现了 AnkG，它在早期发育过程中及时组装节旁连接发挥作用。然而，少突胶质细胞 AnkG 在老年小鼠中的功能仍然未知。我们将确定少突胶质细胞中 AnkG 的功能，更具体地说是 BDex 的功能。我们将定义少突胶质细胞中含有 BDex 的 AnkG 的精确位置。我们将使用功能丧失和功能获得小鼠模型来研究少突胶质细胞 ANK3 变异在大脑中的作用。我们将检查节点和旁节点结构、髓磷脂、有髓轴突生理学和行为。总之，这些研究将开始揭示少突胶质细胞 AnkG 和 BDex AnkG 的作用，并可能揭示对 ANK3 相关神经精神疾病的分子病理生理学的见解。