Wdr62 in neural development and malformations of cortical development disease

Wdr62 在神经发育和皮质发育畸形疾病中的作用

基本信息

批准号：
8995674
负责人：
Jianfu Chen
金额：
$ 24.17万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8995674
关键词：
Affinity Chromatography Alleles Bacterial Artificial Chromosomes Behavior Brain Brain Diseases Cell Cycle Cell Proliferation Cell physiology Centrosome Congenital Abnormality Cortical Malformation Data Development Developmental Disabilities Disease Electroporation Etiology Exhibits Fibroblast Growth Factor Foundations Generations Genes Genetic study Goals Human Human Genetics Immigration Individual Interphase Interphase Cell Knock-out Knockout Mice Knowledge Lead Ligase Link Mediating Medical Mentors Methods Microcephaly Mitotic spindle Mus Mutant Strains Mice Mutate Mutation Neural Tube Defects Neurons Phase Physiological Plant Roots Proteins Regulatory Element Role Signal Transduction Testing Transgenic Mice base genetic approach improved in utero in vitro testing in vivo insight loss of function malformation in cortical development migration mouse model mutant nerve stem cell nervous system disorder neurodevelopment neurogenesis novel protein function relating to nervous system self-renewal spatiotemporal ubiquitin-protein ligase

项目摘要

ABSTRACT: Malformations of cortical development (MCD) represent a major cause of developmental disabilities and are at the root of numerous neurological disorders. Although human genetic studies have established a link between a class of centrosome proteins and MCD, the in vivo functions of these proteins and the pathophysiological mechanisms of MCD diseases remain obscure. Focusing on one MCD disease- associated gene Wdr62, which encodes a centrosome protein, the goals of this proposal are to determine the in vivo roles and functional mechanisms of Wdr62 during normal cortical development and to investigate how Wdr62 mutations lead to a wide spectrum of MCD disorders. Three specific aims are proposed over the next 5 years. The first is to use mouse genetic approaches to determine the developmental and cellular functions of Wdr62 in normal cortical development. The second is to test the in vitro and in vivo roles of individual Wdr62 disease-associated mutations during cortical development. My last aim is to develop a new affinity purification method to identify the regulators that mediate WDR62 functions from developing mouse brains. These studies will advance the field not only by providing novel insights into the physiological functions and mechanisms of action of Wdr62, but also by contributing fundamental knowledge to elucidate the etiologies of MCD diseases.

摘要：皮质发育（MCD）的畸形是发展的主要原因残疾，是许多神经系统疾病的根源。尽管人类遗传研究有建立了一类中心体蛋白与MCD之间的联系，这些蛋白质的体内功能和 MCD疾病的病理生理机制仍然晦涩难懂。专注于一种MCD疾病 - 编码中心体蛋白的相关基因WDR62，该提案的目标是确定IN 正常皮质发育过程中WDR62的体内角色和功能机制，并研究如何 WDR62突变导致广泛的MCD疾病。在接下来的5个中提出了三个具体目标年。首先是使用小鼠遗传方法来确定正常皮质发育中的WDR62。第二个是测试单个WDR62的体外和体内角色皮质发育过程中与疾病相关的突变。我最后的目标是开发新的亲和力净化识别介导WDR62功能的调节器从发育中的大脑中介导的方法。这些研究不仅可以通过提供对生理功能和机制的新见解来推进领域 WDR62的作用，也是通过促进基本知识来阐明MCD疾病的病因的。