Genetic Mechanisms in Cerebellum Malformations

小脑畸形的遗传机制

基本信息

批准号：
8051677
负责人：
BRUCE A HAMILTON
金额：
$ 31.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-07 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8051677
关键词：
Affect Alleles Animals Anterior Apoptotic Binding Biological Assay Birth Cell Differentiation process Cell Proliferation Cells Cerebellar malformation Cerebellar vermis structure Cerebellum Characteristics Childhood Complementary DNA Congenic Strain Dandy-Walker Syndrome Data Defect Dependence Detection Development Diagnosis Disease Experimental Models Family Fourth ventricle structure Funding Genes Genetic Genetic Crosses Genetic Transcription Genetic screening method Genomics Homozygote Human In Situ Label Location Malignant neoplasm of brain Measurement Methods Molecular Molecular Profiling Molecular Target Mutation Pathway interactions Patients Pattern Phenotype Positioning Attribute Posterior Fossa Preparation Primordium Proliferating Proteins RNA Interference Regulation Research Personnel Role Rotation Series Severities Signal Pathway Signal Transduction Signaling Molecule Site Slice Source Staging Structure Structure of choroid plexus Syndrome Testing Therapeutic Time Variant Viral Work Zinc Fingers base chromatin immunoprecipitation clinically significant developmental genetics genome-wide hindbrain in vivo malformation miniaturize mouse model mutant nerve stem cell nervous system disorder null mutation positional cloning precursor cell programs promoter response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Disruptions in the normal development of the cerebellum result in clinically significant malformations whose mechanistic bases are poorly understood. This proposal uses a combination of established and emerging genetic and genomic methods to dissect molecular mechanisms of cerebellar vermis malformation in a new mouse model resembling Dandy-Walker malformations. Homozygotes for the nur12 mutation show show nearly complete agenesis of the vermis and choroid plexus, cystic dilation of the fourth ventricle, and anterior malrotation of cerebellar structures within the posterior fossa. As preliminary data for defining molecular mechanisms relevant to features shared between this mutant and human patients, the applicant has identified a null mutation of a zinc finger transcription in nur12 mutants. The applicant has begun to identify developmental sequelae to this mutation, including profound effects on proliferation of neural progenitor cells. The three specific aims will (1) establish an allelic series at the locus and investigate sources of interindividual variation in the severity (hemispheric involvement) of null allele; (2) define cellular and developmental mechanisms of the nur12 malformation, including tests for the roles of BMP/SMAD and EBF signaling pathway, through a combination of in situ labeling, marker gene analyses and signaling response measurements in culture; and (3) identify molecular targets of ZFP423 activity in cerebellum development by transcriptional profiling at sequential stages of development and by identifying overlaps in promoter occupancy among ZFP423, BMP-activated SMADs and EBF factors using a highly parallel platform for genome-wide location analysis for transcription factor binding. Relevance: This proposal will identify mechanisms relevant to the Dandy-Walker malformation - a severe defect found in 1/25,000 -1/30,000 births. Preliminary results suggest that the mechanisms acting here affect the ability of precursor cells to continue dividing, which may have therapeutic application for both prenatally diagnosed malformations and pediatric brain cancers.

描述（由申请人提供）：小脑正常发育中的破坏会导致临床上明显的畸形，其机械基础知之甚少。该提案结合了已建立和新兴的遗传和基因组方法的组合，在类似于花花公子walk畸形的新小鼠模型中剖析小脑vermis畸形的分子机制。 NUR12突变的纯合子显示，几乎完整的vermis和脉络丛，第四脑室的囊性扩张以及后孔内小脑结构的前畸形。作为定义与该突变体和人类患者共享特征相关的分子机制的初步数据，申请人已经确定了NUR12突变体中锌指转录的无效突变。申请人已经开始确定这种突变的发育后遗症，包括对神经祖细胞增殖的深远影响。这三个特定目的（1）将在该基因座建立一个等位基因系列，并研究无效等位基因严重程度（半球参与）的个体差异来源；（2）定义NUR12畸形的细胞和发育机制，包括测试BMP/SMAD和EBF信号通路的作用，通过原位标记，标记基因分析和信号反应测量在培养中的结合；（3）通过转录分析在发育的顺序阶段进行转录分析，并通过识别ZFP423之间的启动子占用物的重叠，BMP激活的SMADS和EBF因子使用高度平行的基因组位置分析转录因子结合。相关性：该提案将确定与Dandy -Walker畸形相关的机制，这是1/25,000 -1/30,000出生中的严重缺陷。初步结果表明，此处作用的机制会影响前体细胞继续分裂的能力，这可能在产前诊断的畸形和小儿脑癌中具有治疗性应用。