22q11 Genes and Complex Behavior in Mice
22q11 基因和小鼠的复杂行为
基本信息
- 批准号:7388623
- 负责人:
- 金额:$ 24.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-02-01 至 2010-01-31
- 项目状态:已结题
- 来源:
- 关键词:22q1122q11.2AdultAffectAttention deficit hyperactivity disorderAttenuatedBehaviorBehavior DisordersBehavioralBehavioral MechanismsBiological ModelsBoxingBrainCardiovascular systemCell divisionChromosomes, Human, Pair 16ComplexConflict (Psychology)Congenital Heart DefectsDataDefectDiGeorge SyndromeDiseaseGenesGeneticGoalsHereditary DiseaseHomologous GeneHumanHyperactive behaviorIndividualKnockout MiceLightMental DepressionMotor ActivityMusNatureObsessive-Compulsive DisorderOutcomePhenotypePredispositionPrincipal InvestigatorProteinsRateReportingRodentRoleSchizophreniaShprintzen syndromeSocial BehaviorSocial InteractionSocial isolationSolidSymptomsSystemTestingThymus GlandViral Vectorbasecraniofacialdevelopmental diseasegene interactioninnovationknockout genemiddle earmouse modelneuropsychiatrynovelpostnatalprepulse inhibitionprotein expressionresearch studyrestorationtranscription factor
项目摘要
DESCRIPTION (provided by applicant): DiGeorge syndrome (DGS)/velo-cardio-facial syndrome (VCFS) is one of the common genetic disorders and affects approximately one in 4000 livebirths. Hemizygosity of a 1.5-3.0 Mb region of the human 22q11 underlies various neuropsychiatric, behavioral and physical abnormalities in DGS/VCFS. They include behavioral excitation, impaired prepulse inhibition, social interaction problems, as well as cardiovascular defects. Although efforts have been made in identifying individual 22q11 genes responsible for the behavioral abnormalities of DGS/VCFS, little is known about how individual 22q11 genes interact in increasing the susceptibility to these behavioral abnormalities. We and others have shown that deletion of either the T-box transcription factor Tbx1 or Cdcrel (cell division control related protein, also called Sept5) induces some, but not all DGS/VCFS symptoms in mice. To study the interactive role of Tbx1 and Cdcrel, the Principal Investigator has developed a double Tbx1/Cdcrel heterozygous mouse. Using this mouse line together with Tbx1 heterozygous mice and Cdcrel heterozygous/knockout mice, we have further shown that mice with combined heterozygosity of Tbx1 and Cdcrel, but not mice with deletion of either Tbx1 or Cdcrel alone, have sensitized hyperactivity. This suggests that Tbx1 and Cdcrel synergistically increase the susceptibility to the behavioral abnormalities of DGS/VCFS. Our long-term goal is to ascertain the nature of interaction among 22q11 genes as one of the underlying mechanisms for the behavioral abnormalities of DGS/VCFS. The specific hypothesis to be tested in this R21 proposal is that Tbx1 and Cdcrel interactively contribute to distinct behavioral abnormalities in mice. The specific aims to test this hypothesis are: Specific Aim 1: To determine whether heterozygosity of Tbx1, Cdcrel, or their combination causes abnormalities in locomotor activity/habituation, prepulse inhibition and social behaviors in mice (Experiments 1- 3). We will use Tbx1 heterozygous mice, Cdcrel heterozygous and knockout mice, double Tbx1/Cdcrel heterozygous mice, and their wild-type littermates. Specific Aim 2: To determine whether behavioral abnormalities seen in double heterozygous mice are attenuated by restoration of Cdcrel by a viral vector in the brain (Experiment 4). The present R21 proposal will provide a mouse model to further ascertain the nature of interaction between Tbx1 and Cdcrel in the brain in relation to behavioral abnormalities. The proposal will form a solid basis to further study the genetic basis of this common developmental disorder. Because deletion of 22q11 is also associated with high rates of schizophrenia, obsessive compulsive disorder, and attention deficit hyperactivity disorder, the outcome of this project will have significant implications for a better understanding of the genetic mechanisms of these neuropsychiatric disorders as well. The proposed project will ascertain the role of two 22q11 genes in behavioral abnormalities in a double heterozygous mouse model. Because hemizygosity of this chromosomal region is associated with many neuropsychiatric disorders and behavioral abnormalities, the outcome of the proposed studies will contribute to a better understanding of the genetic mechanisms underlying neuropsychiatric disorders, including schizophrenia.
描述(由申请人提供):DiGeorge综合征(DGS)/腭心面综合征(VCFS)是常见的遗传性疾病之一,大约每4000例活产中就有1例受影响。人类22 q11的1.5-3.0 Mb区域的半合子是DGS/VCFS中各种神经精神、行为和身体异常的基础。它们包括行为兴奋、前脉冲抑制受损、社会交往问题以及心血管缺陷。虽然已经努力确定个别22 q11基因负责DGS/VCFS的行为异常,很少有人知道个别22 q11基因如何相互作用,增加这些行为异常的易感性。我们和其他人已经表明,T-box转录因子Tbx 1或Cdcrel(细胞分裂控制相关蛋白,也称为Sept 5)的缺失会诱导小鼠的一些但不是所有DGS/VCFS症状。为了研究Tbx 1和Cdcrel的相互作用,主要研究者开发了双Tbx 1/Cdcrel杂合子小鼠。将该小鼠系与Tbx 1杂合小鼠和Cdcrel杂合/敲除小鼠一起使用,我们进一步表明,具有Tbx 1和Cdcrel的组合杂合性的小鼠,而不是具有单独的Tbx 1或Cdcrel缺失的小鼠,具有致敏性多动症。这表明Tbx 1和Cdcrel协同增加对DGS/VCFS行为异常的易感性。我们的长期目标是确定22 q11基因之间的相互作用的性质作为DGS/VCFS行为异常的潜在机制之一。在这个R21提案中要测试的特定假设是Tbx 1和Cdcrel交互地导致小鼠中的不同行为异常。具体目的1:确定Tbx 1、Cdcre 1或其组合的杂合性是否导致小鼠的运动活动/习惯化、前脉冲抑制和社会行为异常(实验1- 3)。我们将使用Tbx 1杂合小鼠、Cdcrel杂合和敲除小鼠、双Tbx 1/Cdcrel杂合小鼠及其野生型同窝仔。具体目标二:为了确定在双杂合小鼠中观察到的行为异常是否通过脑中的病毒载体恢复Cdcrel而减弱(实验4)。目前的R21提案将提供小鼠模型,以进一步确定Tbx 1和Cdcrel在大脑中与行为异常相关的相互作用的性质。该提案将为进一步研究这种常见发育障碍的遗传基础奠定坚实的基础。由于22 q11的缺失也与精神分裂症、强迫症和注意缺陷多动障碍的高发病率相关,因此该项目的结果也将对更好地理解这些神经精神疾病的遗传机制产生重大影响。该项目将确定两个22 q11基因在双杂合小鼠模型中行为异常的作用。由于该染色体区域的半合子与许多神经精神疾病和行为异常相关,因此拟议研究的结果将有助于更好地了解神经精神疾病(包括精神分裂症)的遗传机制。
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)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Noboru Hiroi其他文献
Noboru Hiroi的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Noboru Hiroi', 18)}}的其他基金
Predicting the developmental trajectories of cognitive and motor dimensions from preterm neonatal vocalizations
从早产儿发声预测认知和运动维度的发育轨迹
- 批准号:
10315460 - 财政年份:2021
- 资助金额:
$ 24.57万 - 项目类别:
Predicting the developmental trajectories of cognitive and motor dimensions from preterm neonatal vocalizations
从早产儿发声预测认知和运动维度的发育轨迹
- 批准号:
10463851 - 财政年份:2021
- 资助金额:
$ 24.57万 - 项目类别:
Structure and Function of Neonatal Social Communication in Genetic Mouse Models of Autism
自闭症遗传小鼠模型中新生儿社交沟通的结构和功能
- 批准号:
10220931 - 财政年份:2017
- 资助金额:
$ 24.57万 - 项目类别:
Structure and Function of Neonatal Social Communication in Genetic Mouse Models of Autism
自闭症遗传小鼠模型中新生儿社交沟通的结构和功能
- 批准号:
10005276 - 财政年份:2017
- 资助金额:
$ 24.57万 - 项目类别:
Postnatal mechanisms of cognitive development in mice
小鼠认知发展的产后机制
- 批准号:
10539977 - 财政年份:2013
- 资助金额:
$ 24.57万 - 项目类别:
Postnatal mechanisms of cognitive development in mice
小鼠认知发展的产后机制
- 批准号:
10657796 - 财政年份:2013
- 资助金额:
$ 24.57万 - 项目类别:
相似国自然基金
22q11.2染色体微重复影响TOP3B表达并导致腭裂发生的机制研究
- 批准号:82370906
- 批准年份:2023
- 资助金额:48.00 万元
- 项目类别:面上项目
22q11.2微缺失综合症中T盒转录因子Tbx1与信号接头蛋白Crkl遗传相互作用致肺动脉发育不良缺陷的机制研究
- 批准号:81170153
- 批准年份:2011
- 资助金额:60.0 万元
- 项目类别:面上项目
基于染色体22q11.2候选基因与腭心面综合征表型的分子诊断研究
- 批准号:81070813
- 批准年份:2010
- 资助金额:35.0 万元
- 项目类别:面上项目
无22q11.2区基因微缺失的心脏圆锥动脉干畸形患者中新TBX1突变体蛋白的功能研究
- 批准号:81070135
- 批准年份:2010
- 资助金额:32.0 万元
- 项目类别:面上项目
染色体22q11.2区域泌尿系统畸形关键致病基因的克隆与鉴定
- 批准号:30571867
- 批准年份:2005
- 资助金额:25.0 万元
- 项目类别:面上项目
相似海外基金
成人期へtransitionする22q11.2欠失症候群患者の移行支援プログラムの構築
为 22q11.2 缺失综合征患者过渡到成年期建立过渡支持计划
- 批准号:
24K13915 - 财政年份:2024
- 资助金额:
$ 24.57万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
An Engineered Hydrogel Platform to Improve Neural Organoid Reproducibility for a Multi-Organoid Disease Model of 22q11.2 Deletion Syndrome
一种工程水凝胶平台,可提高 22q11.2 缺失综合征多器官疾病模型的神经类器官再现性
- 批准号:
10679749 - 财政年份:2023
- 资助金额:
$ 24.57万 - 项目类别:
重複障害を呈する医療的ケア児と家族の移行期における意思決定支援のPPI型研究
多重残疾儿童及其家庭过渡期决策支持的PPI型研究
- 批准号:
23H02834 - 财政年份:2023
- 资助金额:
$ 24.57万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Outcomes and disease burden in a model of young adult multimorbidity
年轻成人多重病模型的结果和疾病负担
- 批准号:
479042 - 财政年份:2023
- 资助金额:
$ 24.57万 - 项目类别:
Operating Grants
22q11.2欠失症候群との網羅的な比較検討によるファロー四徴症での遺伝子異常の解明
与22q11.2缺失综合征综合比较阐明法洛四联症遗传异常
- 批准号:
23K08237 - 财政年份:2023
- 资助金额:
$ 24.57万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Investigating abnormalities in top-down cortical processing and behavior in a model of the 22q11.2 deletion
研究 22q11.2 缺失模型中自上而下的皮质处理和行为的异常
- 批准号:
10649058 - 财政年份:2023
- 资助金额:
$ 24.57万 - 项目类别:
Phenotypic convergence at mitochondria in copy number variant disorders
拷贝数变异性疾病中线粒体的表型趋同
- 批准号:
10723885 - 财政年份:2023
- 资助金额:
$ 24.57万 - 项目类别:
Neurodevelopmental defects of the thalamocortical pathway as a convergent feature of psychiatric disorders
丘脑皮质通路的神经发育缺陷是精神疾病的共同特征
- 批准号:
10655225 - 财政年份:2023
- 资助金额:
$ 24.57万 - 项目类别:
Improving Genetic Diagnosis for African Ancestry Populations
改善非洲血统人群的基因诊断
- 批准号:
10736833 - 财政年份:2023
- 资助金额:
$ 24.57万 - 项目类别:
The schizophrenia-associated 3q29 deletion: genetic architecture of behavioral phenotypes
精神分裂症相关的 3q29 缺失:行为表型的遗传结构
- 批准号:
10579244 - 财政年份:2023
- 资助金额:
$ 24.57万 - 项目类别: