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：
8517167
负责人：
Jianfu Chen
金额：
$ 9.23万
依托单位：
UNIVERSITY OF COLORADO DENVER
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 2014-01-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517167
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 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 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：皮质发育的畸形（MCD）代表了发育障碍的主要原因，并且是多种神经系统疾病的根源。尽管人类遗传研究已经在一类中心蛋白和MCD之间建立了联系，但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。该提案的目标是专注于一个编码中心体蛋白的一种MCD疾病相关的基因WDR62，目的是确定正常皮质发育过程中WDR62的体内作用和功能机制，并研究WDR62突变如何导致MCD疾病的广泛范围。在未来5年内提出了三个具体目标。首先是使用小鼠遗传方法来确定正常皮质发育中WDR62的发育和细胞功能。第二个是在皮质发育过程中测试单个WDR62疾病相关突变的体外和体内作用。我的最后一个目的是开发一种新的亲和力纯化方法，以识别介导WDR62功能的调节剂，从发育中的小鼠大脑中介导。这些研究不仅将通过提供有关WDR62作用的生理功能和机制的新颖见解，还将通过促进基本知识来阐明MCD疾病的病因来推进该领域。