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）：人类纤毛功能受损会导致严重的大脑异常和认知障碍。然而，人们对这类称为纤毛病的疾病中大脑畸形的分子机制知之甚少。 ARL13B 和 INPP5E 的隐性突变会导致 Joubert 综合征及相关疾病 (JSRD)，这是一种由特定后脑异常（即磨牙征）定义的人类纤毛病。在这里，我们建议使用 JSRD 致病基因（Arl13b、Inpp5e）及其 JSRD 致病人类突变的小鼠模型来系统地描述 JSRD 脑畸形的机制基础。为了实现这一目标，我们将从功能上表征由导致后脑异常的 ARL13B、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。这项工作的结果将定义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，分子级联和神经发育途径的破坏与纤毛病中脑畸形的发展密切相关，对分子级联和神经发育途径的描述将使我们能够为这些脑部疾病设计最佳的诊断和治疗策略。