Cellular and Molecular Mechanisms in Periventricular Heterotopia

脑室周围异位的细胞和分子机制

基本信息

批准号：
7729307
负责人：
VOLNEY L SHEEN
金额：
$ 29.75万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7729307
关键词：
ADP-Ribosylation Factors Accounting Actin-Binding Protein Actins Address Adherens Junction Affect Apical Autopsy Binding Binding Sites Brain Brain Diseases Brefeldin A Bromodeoxyuridine Capsid Proteins Cell Adhesion Cell Cycle Cell Death Cells Cerebral cortex Cerebrum Coated vesicle Collection Cortical Malformation Cyclic AMP-Dependent Protein Kinases Cytoskeleton Data Defect Development Developmental Delay Disorders Disease Epilepsy Epithelium Exhibits Failure Functional disorder Gait Gene Mutation Genes Goals Growth Guanine Guanine Nucleotide Exchange Factors Human Human Identifications Humulus Hydrocephalus Immigration Impairment Lateral Lead Length Link Location Mediating Membrane Mental Retardation Microcephaly Microfilaments Molecular Morphology Mus Mutate Mutation Neuroepithelial Cells Neurons Nodule Pathway interactions Phenotype Phosphorylation Phosphorylation Site Phosphotransferases Proteins Regulation Role SNAP receptor Sampling Scaffolding Protein Signal Transduction Signaling Molecule Testing Therapeutic Intervention Transport Vesicles Ventricular Vesicle alpha-SNAP brain malformation cell motility extracellular filamin gene function lateral ventricle malformation migration mouse model mutant nerve stem cell nervous system disorder neurodevelopment neuroepithelium periventricular heterotopia positional cloning progenitor public health relevance receptor binding relating to nervous system soluble NSF attachment protein trafficking

项目摘要

DESCRIPTION (provided by applicant): Developmental failures in neuronal migration in the cerebral cortex result in epilepsy and mental retardation. Moreover, disorders in neural development account for a broad set of neurological diseases. Positional cloning has led to the identification of human genes mutated in periventricular heterotopia (PH), a malformation of cortical development characterized by the failure of a subset of neurons to migrate from the ventricle during cerebral cortical development. Mutations in either of two genes, the actin-binding filamin A (FLNA) and the vesicle transport related ARFGEF2, leads to severe defects in the initial migration of neurons along the ventricular lining and produces nearly identical radiographic findings of PH in humans. Mutations in the Napa gene in mice also lead to heterotopic nodules strikingly similar to those seen in humans. The central hypothesis of this application is that these common mutant phenotypes result from direct interactions between the encoded proteins or from a shared common pathway. The proposed functions of FLNA and ARFGEF2 appear quite disparate with FLNA implicated in neuronal motility due to its interactions with the actin cytoskeleton and BIG2 (encoded by ARFGEF2) involved in vesicle trafficking through its guanine exchange regulation of the ADP-ribosylation factors (ARFs). ARF activation is required during the assembly of protein coats for vesicle budding. Alpha-SNAP (encoded by Napa) is a NSF attachment protein, involved in SNAP receptor-mediated vesicle fusion. Collectively, however, all of these genes are involved in endosomal vesicle trafficking, either through regulation of actin filaments needed for transport, assembly of the coat protein, or fusion of the vesicle to the membrane. Thus, the role of FLNA and ARFGEF2 in giving rise to PH may share a common pathogenic mechanism with Napa by control over endosomal vesicle transport. Therefore the Specific Aims of this proposal are to determine: 1) which cellular defects seen following loss of FLNA function in mice contribute to PH formation, 2) whether FLNA binds BIG2 and directs BIG2 localization and BIG2-dependent ARF activation, and 3) whether loss of Napa or ARFGEF2 function in neural progenitors alters apical and/or basal adherens junctions leading to PH formation. PUBLIC HEALTH RELEVANCE: Human mutations in several genes are known to cause nearly identical brain malformations and result in epilepsy and mental retardation. The current proposal seeks to understand the cellular and molecular mechanisms of these genes, and how their function might be interrelated given their shared phenotype. Understanding the pathophysiology of human brain disorders provides a means for the development of therapeutic interventions.

描述（由申请人提供）：大脑皮层中神经元迁移的发育失败导致癫痫和智力低下。此外，神经发育中的疾病会导致广泛的神经系统疾病。位置克隆导致鉴定在脑室周围异位症（pH）中突变的人基因，这是一种皮质发育的畸形，其特征是神经元子集失败，无法在脑皮质发育过程中从心室迁移。两个基因中的任何一个突变，即肌动蛋白结合丝蛋白A（FLNA）和囊泡转运相关的ARFGEF2，导致神经元沿心室内衬的初始迁移的严重缺陷，并在人类中产生pH值几乎相同的放射学发现。小鼠NAPA基因中的突变也导致异位结节与人类所见的结节非常相似。该应用的中心假设是，这些常见的突变表型是由编码蛋白或共享共同途径之间的直接相互作用引起的。 FLNA和ARFGEF2的拟议功能似乎完全不同，与神经元运动有关的FLNA与肌动蛋白细胞骨架和BIG2的相互作用（由ARFGEF2编码）（通过其通过其ADP-核糖基化因子的鸟嘌呤交换调节）（ARFS）相互作用（ARFGEF2编码）。在组装蛋白质涂层的过程中，需要激活ARF激活。 α-SNAP（由NAPA编码）是NSF附着蛋白，参与了SNAP受体介导的囊泡融合。然而，所有这些基因都通过调节运输所需的肌动蛋白丝，涂层蛋白的组装或囊泡融合到膜上所需的肌动蛋白丝进行总体涉及内体囊泡运输。因此，FLNA和ARFGEF2在产生pH值中的作用可能通过控制内体囊泡转运而与NAPA共享常见的致病机制。 Therefore the Specific Aims of this proposal are to determine: 1) which cellular defects seen following loss of FLNA function in mice contribute to PH formation, 2) whether FLNA binds BIG2 and directs BIG2 localization and BIG2-dependent ARF activation, and 3) whether loss of Napa or ARFGEF2 function in neural progenitors alters apical and/or basal adherens junctions leading to PH formation.公共卫生相关性：已知几种基因中的人类突变会引起几乎相同的脑畸形，并导致癫痫和智力低下。当前的提案试图了解这些基因的细胞和分子机制，以及它们的功能如何相互关联。了解人脑疾病的病理生理学为发展治疗干预提供了一种手段。