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Molecular Mechanisms of Primary Microcephaly

原发性小头畸形的分子机制

基本信息

批准号：
8482402
负责人：
Angeliki Louvi
金额：
$ 34.52万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8482402
关键词：
Address Affect Animal Model Apoptosis Behavior Biological Biological Assay Biology Brain Cell Culture Techniques Cell Cycle Cell Cycle Regulation Cell division Cell physiology Cortical Malformation Defect Development Disease Down-Regulation Embryo Event Gene Expression Profile Genes Goals Head Human In Vitro Individual Informatics Link Maps Mediating Mental Retardation Microcephaly Microgyria Mitosis Modeling Molecular Molecular Genetics Molecular Profiling Monitor Multiprotein Complexes Mus Mutation Neocortex Neuroepithelial Cells Neurons Pathway interactions Patients Phenocopy Phenotype Play Proteins Proteomics Research Role Signal Pathway Signal Transduction Stem cells Testing Validation Variant WD Repeat Work base brain malformation comparative in vitro Assay in vivo inhibitor/antagonist insight lissencephaly migration mouse model neocortical nerve stem cell novel protein complex public health relevance small hairpin RNA tool

项目摘要

DESCRIPTION (provided by applicant): The objective of this application is to examine the molecular mechanisms underlying Autosomal Recessive Primary Microcephaly. It is based on the identification of homozygous mutations in WDR62 in individuals with primary microcephaly and a wide spectrum of structural brain abnormalities and aims to gain mechanistic insights into the biology of WDR62 in mammalian brain development. The proposed research test the hypothesis that WDR62 functions in cortical development by controlling cell cycle dynamics, survival or neural progenitors, and/or migration of neurons. It aims to a) determine the cellular function of WDR62; b) establish the functional interacting partners of WDR62 in the developing brain using proteomic approaches and c) examine the relationship of WDR62 with Wnt signaling in the developing brain. The proposed studies carry basic biological value and take advantage of molecular genetic findings that pointed to WDR62 as an important modulator of basic neurodevelopmental mechanisms and implicated its malfunction in a wide spectrum of severe brain malformations.

描述（由申请方提供）：本申请的目的是检查常染色体隐性原发性小头畸形的分子机制。它是基于在患有原发性小头畸形和广泛的脑结构异常的个体中鉴定WDR 62的纯合突变，旨在获得对哺乳动物脑发育中WDR 62生物学的机理见解。这项研究验证了WDR 62通过控制细胞周期动力学、神经祖细胞存活和/或神经元迁移在皮质发育中发挥作用的假设。其目的是a）确定WDR 62的细胞功能; B）使用蛋白质组学方法在发育中的大脑中建立WDR 62的功能相互作用配偶体;以及c）检查WDR 62与发育中的大脑中的Wnt信号传导的关系。拟议的研究具有基本的生物学价值，并利用分子遗传学发现，这些发现指出WDR 62是基本神经发育机制的重要调节剂，并在广泛的严重脑畸形中涉及其功能障碍。