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Mechanisms underlying Joubert syndrome related brain malformations

朱伯特综合征相关脑畸形的潜在机制

基本信息

批准号：
8929484
负责人：
EVA S ANTON
金额：
$ 51.09万
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：
2014
资助国家：
美国
起止时间：
2014-09-28 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8929484
关键词：
Address Alleles Animals Architecture Axon Bardet-Biedl Syndrome Behavior Disorders Brain Brain Diseases Breathing Cells Cerebellar vermis structure Cerebellum Cerebral cortex Cerebrum Cilia Clinical Code Communities Comprehension Congenital cerebellar hypoplasia Defect Development Diagnosis Diagnostic Disease Exhibits Foundations Functional disorder G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gene Mutation Genes Goals Growth Cones Health Human Immigration Impaired cognition Intellectual functioning disability Interneurons Joubert syndrome Knowledge Lead Link Magnetic Resonance Imaging Mediating Modeling Molar tooth Molecular Mus Mutant Strains Mice Mutation Neurons Outcome Pathway interactions Patients Phenotype Play Positioning Attribute Proteins Receptor Signaling Regulation Regulator Genes Role Signal Pathway Signal Transduction Symptoms Testing Therapeutic Therapeutic Intervention Variant Vision Work axon guidance brain malformation ciliopathy disease phenotype hindbrain malformation mouse model neurobehavioral neurodevelopment neuron development neuronal cell body novel optogenetics progenitor signal processing smoothened signaling pathway

项目摘要

DESCRIPTION (provided by applicant): Disrupted cilia function in humans results in profound brain abnormalities and cognitive impairments. However, little is known about the molecular mechanisms underlying the brain malformation in this class of disease, called ciliopathies. Recessive mutations in ARL13B and INPP5E cause Joubert Syndrome and Related Disorders (JSRD), a human ciliopathy defined by a specific hindbrain abnormality, the molar tooth sign. Here, we propose to use mouse models of JSRD causing genes (Arl13b, Inpp5e) and their JSRD-causing human mutations to systematically delineate the mechanistic underpinnings of the brain malformations in JSRD. Towards this goal, we will functionally characterize the cilia-dependent or cilia-independent signaling mechanisms triggered by ARL13B, INPP5E gene mutations that lead to hindbrain abnormalities. The outcome of this work will define the role of primary cilia signaling during neuronal development and connectivity. Importantly, delineation of molecular cascades and neurodevelopmental pathways, whose disruptions are integrally related to the development of brain malformations in ciliopathies will enable us to devise optimal diagnostic and therapeutic strategies for these brain disorders.

描述（由申请人提供）：人类纤毛功能中断会导致严重的大脑异常和认知障碍。然而，很少有人知道这类疾病，称为纤毛病变的脑畸形的分子机制。ARL13 B和INPP5E的隐性突变会导致Joubert综合征及相关疾病（JSRD），这是一种由特定的后脑异常（臼齿征）定义的人类纤毛病。在这里，我们建议使用小鼠模型的JSRD引起的基因（Arl13b，Inpp5e）和他们的JSRD引起的人类突变，系统地描绘了JSRD脑畸形的机制基础。为了实现这一目标，我们将在功能上表征由ARL13 B，INPP5E基因突变触发的纤毛依赖性或纤毛非依赖性信号传导机制，这些突变导致后脑异常。这项工作的结果将确定初级纤毛信号在神经元发育和连接过程中的作用。重要的是，分子级联反应和神经发育途径，其中断是整体相关的纤毛病变的脑畸形的发展，将使我们能够制定最佳的诊断和治疗策略，这些脑疾病的划定。