The Role of ARX in Normal and Abnormal Brain Development
ARX 在正常和异常大脑发育中的作用
基本信息
- 批准号:7822783
- 负责人:
- 金额:$ 47.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-02-15 至 2014-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectBindingBrainC-terminalCell DeathChildChildhoodCorpus CallosumCryptogenic West SyndromeDNADataDefectDevelopmentDiagnosisDiseaseDyskinetic syndromeEncephalopathiesEpilepsyExhibitsFemaleFrequenciesFunctional disorderGene ExpressionGene MutationGene ProteinsGene TargetingGenesGenitaliaGrantHealthcareHeterozygoteHomeoboxHomeobox GenesHumanInfantile spasmsInterneuronsInvoluntary MovementsKnock-in MouseLeadLifeLinkMental RetardationMethylationMissense MutationMolecularMusMutant Strains MiceMutationMutation AnalysisNeurologicNeuronsNuclear InclusionPathogenesisPathway interactionsPatientsPhenocopyPhenotypePoly APreventionProteinsRadialRecurrenceRoleSeizuresSeriesSeveritiesSiteStructureSyndromeTestingUnited StatesVariantVentricularWorkX Inactivationautism spectrum disorderbaseboysbrain malformationcell motilitycohortdevelopmental diseaseearly childhoodgene repressionhomeodomainhuman femalein vivoinfancyinterestlissencephalyloss of functionmalemalformationneocorticalnervous system disorderpolyalanineprotein foldingpublic health relevanceresearch studysextranscription factor
项目摘要
DESCRIPTION (provided by applicant): Developmental anomalies of the brain, including mental retardation and malformations, occur in approximately 2% of all live born children and epilepsy in about 0.5%, placing them among the most common known childhood disorders. Despite this high frequency, the molecular and cellular basis for only a very few disorders has been recently elucidated, while the basis of many more remains unknown. Mutations in the transcription factor ARX have been described in several children with early childhood epilepsy and mental retardation, both with and without associated brain malformations. As predicted in our first application, mutations of this gene prove to be a relatively common cause of mental retardation and infantile epilepsy based on the wide spectrum of severity already apparent in this group of children and a recurrent mechanism for mutation in at least two of the four polyalanine tracts found in the gene. The developmental mechanism by which ARX mutations result in this wide spectrum of problems is incompletely understood, although emerging data implicate disturbances in radial and nonradial cell migration, two pathways required for normal brain development. Based on data generated from this grant in humans and mice, the following hypotheses have been generated: (1) the type of ARX mutation predicts the phenotype in both hemizygous males and heterozygous females; (2) the phenotype in affected female humans and mice correlates with X-inactivation; and (3) Arx with an expanded poly-A tract results in defects in transcriptional repression, ultimate resulting in mice with seizures and mental retardation. To test these hypotheses, a series of experiments are proposed that will discover the mutation types in a large series of male and female patients with candidate phenotypes and determine X-inactivation status. In this application we will focus on elucidating the mechanism of a poly-A tract mutation in causing the neurologic phenotype, and in further understanding the downstream targets of Arx and their role in normal and abnormal brain development and function. The phenotypes in humans and mutant mice with different ARX/Arx mutations will be analyzed and compared to each other and to overlapping phenotypes caused by mutations of related genes. These studies are expected to provide a greater understanding of how Arx functions in normal and abnormal development, and will contribute to our understanding of the pathogenesis of such common disorders in children as mental retardation, epilepsy, and structural anomalies of the brain. PUBLIC HEALTH RELEVANCE: Epilepsy and mental retardation co-exist in many children and together extract a significant financial burden on the US health care dollar, an estimated $51.2 billion (in 2003 dollars). Although 3-5% of all children in the United States exhibit epilepsy and/or mental retardation, the underlying pathogeneses for these disorders is poorly understood in most cases. The data from our previous work and from that proposed in this application seeks to understand how one gene, ARX, commonly causes childhood epilepsy and mental retardation. Ultimately we expect these studies will lead to improvements in their diagnosis, treatment, and prevention of these and related neurologic disorders.
描述(申请人提供):大脑发育异常,包括智力低下和畸形,约占所有活着出生的儿童的2%,癫痫约占0.5%,使他们成为最常见的已知儿童疾病之一。尽管这种频率很高,但最近只有极少数疾病的分子和细胞基础被阐明,而更多疾病的基础仍不清楚。转录因子ARX的突变已经在几个患有早期癫痫和智力低下的儿童中被描述,包括有或没有相关的脑畸形。正如我们在第一次应用中预测的那样,该基因的突变被证明是导致智力低下和婴儿癫痫的一种相对常见的原因,因为在这组儿童中已经出现了广泛的严重程度,并且该基因中发现的四条聚丙氨酸中至少有两条是突变的反复机制。ARX突变导致如此广泛的问题的发育机制尚不完全清楚,尽管新出现的数据表明放射状和非放射状细胞迁移障碍,这两条途径是正常大脑发育所必需的。基于这笔赠款在人类和小鼠身上产生的数据,已经产生了以下假设:(1)ARX突变的类型预测了半合子男性和杂合子女性的表型;(2)受影响的女性人类和小鼠的表型与X-失活相关;(3)带有扩展的Poly-A束的Arx导致转录抑制缺陷,最终导致小鼠癫痫发作和智力低下。为了验证这些假设,我们提出了一系列实验,以发现大量具有候选表型的男性和女性患者的突变类型,并确定X-失活状态。在这一应用中,我们将重点阐明PolyA区突变导致神经表型的机制,并进一步了解Arx下游靶标及其在正常和异常脑发育和功能中的作用。具有不同ARX/ARX突变的人类和突变小鼠的表型将被分析并相互比较,并与相关基因突变引起的重叠表型进行比较。这些研究有望更好地了解ARX在正常和异常发育中的作用,并将有助于我们理解儿童常见疾病的发病机制,如智力低下、癫痫和脑结构异常。与公共卫生相关:癫痫和智力低下在许多儿童中共存,共同给美国的医疗保健带来了巨大的财政负担,估计为512亿美元(按2003年美元计算)。尽管美国有3%-5%的儿童表现出癫痫和/或智力低下,但在大多数情况下,这些疾病的潜在发病机制尚不清楚。我们以前的工作和本申请中提出的数据试图了解ARX基因如何通常导致儿童癫痫和智力低下。最终,我们预计这些研究将导致这些和相关神经疾病的诊断、治疗和预防方面的改进。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Jeffrey A Golden其他文献
ARX regulates interneuron subtype differentiation and migration
ARX 调节中间神经元亚型分化和迁移
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Ginam Cho;Youngshin Lim;Shyam K Akula;Abigail K Myers;Connie Chen;Katherine A Rafael;Christopher A. Walsh;Jeffrey A Golden - 通讯作者:
Jeffrey A Golden
Jeffrey A Golden的其他文献
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{{ truncateString('Jeffrey A Golden', 18)}}的其他基金
Precision models of ARX-associated neurodevelopmental disorders
ARX 相关神经发育障碍的精确模型
- 批准号:
10646390 - 财政年份:2019
- 资助金额:
$ 47.99万 - 项目类别:
Precision models of ARX-associated neurodevelopmental disorders
ARX 相关神经发育障碍的精确模型
- 批准号:
10447194 - 财政年份:2019
- 资助金额:
$ 47.99万 - 项目类别:
Arx Associated Transcriptional Networks in Neocortical Development
新皮质发育中的 Arx 相关转录网络
- 批准号:
9922369 - 财政年份:2018
- 资助金额:
$ 47.99万 - 项目类别:
Arx Associated Transcriptional Networks in Neocortical Development
新皮质发育中的 Arx 相关转录网络
- 批准号:
10158549 - 财政年份:2018
- 资助金额:
$ 47.99万 - 项目类别:
The Role of ARX in Normal and Abnormal Brain Development
ARX 在正常和异常大脑发育中的作用
- 批准号:
8076800 - 财政年份:2005
- 资助金额:
$ 47.99万 - 项目类别:
The Role of ARX in Normal and Abnormal Brain Development
ARX 在正常和异常大脑发育中的作用
- 批准号:
8606909 - 财政年份:2005
- 资助金额:
$ 47.99万 - 项目类别:
The Role of ARX in Normal and Abnormal Brain Development
ARX 在正常和异常大脑发育中的作用
- 批准号:
6875381 - 财政年份:2005
- 资助金额:
$ 47.99万 - 项目类别:
The Role of ARX in Normal and Abnormal Brain Development
ARX 在正常和异常大脑发育中的作用
- 批准号:
7194354 - 财政年份:2005
- 资助金额:
$ 47.99万 - 项目类别:
The Role of ARX in Normal and Abnormal Brain Development
ARX 在正常和异常大脑发育中的作用
- 批准号:
7017781 - 财政年份:2005
- 资助金额:
$ 47.99万 - 项目类别:
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