Cellular and Molecular Mechanisms of Early Cortical Development

早期皮质发育的细胞和分子机制

基本信息

批准号：
8520056
负责人：
ERIC Christopher OLSON
金额：
$ 22.74万
依托单位：
UPSTATE MEDICAL UNIVERSITY
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：
2009-09-30 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8520056
关键词：
Actins Acute Adaptor Signaling Protein Adult Architecture Autistic Disorder Behavior Behavior Control Brain Cell-Cell Adhesion Cells Cerebral cortex Cerebrum Cognition Cortical Malformation Data Defect Development Dyslexia Embryo Epilepsy Etiology Event Exposure to F-Actin Focal Adhesions Healed Health Hereditary Disease Image Indium Infection Ligands Mediating Medical Mental Retardation Modeling Molecular Morphology Movement Mus Neuraxis Neurites Neuronal Differentiation Neurons Phenotype Photons Positioning Attribute Post-Translational Protein Processing Proteins RNA Interference Radiation Reading Disorder Recombinants Recovery of Function Reeler Mouse Reelin Signaling Pathway Regulation Reporter Research Personnel Role Signal Transduction Signaling Protein Staging Structure Testing Time Toxin Universities Work base brain malformation cell motility healing inhibitor/antagonist insight migration nerve injury novel overexpression paxillin polymerization protein expression response

项目摘要

DESCRIPTION (provided by applicant): The developing cerebral cortex is a sensitive target for genetic diseases and for gestational exposure to toxins, infection and radiation. Despite this, the basic cellular and molecular mechanisms of cortical development, particularly early cortical development are not well understood. Using a novel 3D cortical hemisphere explant approach and reporter mice, we will examine the cellular behaviors that initiate cortical plate formation and determine how the secreted ligand, Reelin coordinates these behaviors. We will focus on the role of Reelin-dependent modulation of the focal adhesion adaptor protein Paxillin that we find dynamically expressed during early cortical development and aberrantly expressed in reeler mice cortices that lack Reelin. We are using pharmacological and RNAi-based approaches to target downstream signaling elements in the Reelin signaling pathway to determine Reelin's and Paxillin's role(s) in triggering and/or sustaining this morphological differentiation and motility. These studies will help resolve competing models of Reelin function, while providing further molecular and cellular insights into the formation of a cellular layer of the cerebral cortex. Insight into Reelin's role in cortical development will provide a general insight into the development and organization of neurons throughout the central nervous system. In adults, Reelin is up regulated in epileptic foci, and in response to nerve injury. Reelin may therefore have additional important roles in healing and functional recovery. PUBLIC HEALTH RELEVANCE: Brain malformations are increasingly appreciated as an underlying cause of certain forms of epilepsy, mental retardation, autism, dyslexia and reading disorders. This proposal examines molecular and cellular events that occur at an early stage of brain development, but that have a major impact on later brain function and cognition. The work will provide a framework for understanding the etiology of cerebral cortical malformations.

描述（由申请人提供）：发育中的大脑皮层是遗传性疾病以及妊娠期接触毒素、感染和辐射的敏感目标。尽管如此，皮质发育，特别是早期皮质发育的基本细胞和分子机制尚不清楚。使用新型 3D 皮质半球外植体方法和报告小鼠，我们将检查启动皮质板形成的细胞行为，并确定分泌的配体 Reelin 如何协调这些行为。我们将重点关注粘着斑接头蛋白 Paxillin 的 Reelin 依赖性调节的作用，我们发现 Paxillin 在早期皮质发育过程中动态表达，并在缺乏 Reelin 的 reeler 小鼠皮质中异常表达。我们正在使用药理学和基于 RNAi 的方法来靶向 Reelin 信号通路中的下游信号元件，以确定 Reelin 和 Paxillin 在触发和/或维持这种形态分化和运动中的作用。这些研究将有助于解决 Reelin 功能的竞争模型，同时为大脑皮层细胞层的形成提供进一步的分子和细胞见解。深入了解 Reelin 在皮质发育中的作用将提供对整个中枢神经系统神经元发育和组织的总体了解。在成人中，Reelin 在癫痫病灶以及对神经损伤的反应中表达上调。因此，Reelin 可能在愈合和功能恢复方面发挥着额外的重要作用。公众健康相关性：人们越来越认识到，大脑畸形是某些形式的癫痫、智力低下、自闭症、阅读障碍和阅读障碍的根本原因。该提案研究了大脑发育早期发生的分子和细胞事件，这些事件对后来的大脑功能和认知产生重大影响。这项工作将为理解大脑皮质畸形的病因提供一个框架。