Exploring the role of the protocadherin CELSR3 in Tourette syndrome

探索原钙粘蛋白 CELSR3 在抽动秽语综合征中的作用

基本信息

  • 批准号:
    10532254
  • 负责人:
  • 金额:
    $ 19.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-12-01 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY / ABSTRACT Tourette syndrome (TS) is a neurodevelopmental disorder with a strong genetic component, affecting 0.5-1% of children. TS is characterized by multiple, recurring tics, which are a source of significant disability. The clinical management of TS poses considerable challenges, partially because all available pharmacotherapies are not specific to the pathogenic mechanisms, and thus have only limited efficacy and significant side effects. Understanding the genetic basis of TS is an essential step to elucidate the causes of this disorder; however, until recently, all available information was limited to rare genetic mutations sporadically associated with TS pedigrees, and thus could not be generalized to most patients. Recently, however, evidence from large genetic studies and the first gene-expression analyses of postmortem samples from TS-affected individuals has revealed that protocadherins, a superfamily of proteins regulating cell-cell interactions, play a key role in TS pathogenesis. In support of these findings, the largest whole-exome studies on de novo mutations in TS recently identified the protocadherin-encoding gene CELSR3 as one of the first high-confidence TS risk genes. This R21 proposal seeks to leverage these new discoveries and explore the mechanisms whereby CELSR3 deficiency predisposes to TS, using transgenic mouse models harboring a mutation of this gene. In preliminary studies, we found that juvenile peripubertal male and female CELSR3 heterozygous mice exhibit TS-like phenotypes, including tic-like stereotypies and sensorimotor gating deficits, in comparison with their wild-type littermates. Furthermore, previous experiments showed that CELSR3 has a critical role in interneuron migration and the organization of dopaminergic projections. Based on this background, we hypothesize that partial CELSR3 deficiency leads to TS-related neurobehavioral deficits by impairing the histoarchitectural and molecular organization of the striatum. To test this hypothesis, the two aims of this application will respectively: 1) chart the trajectory of the behavioral impairments of CELSR3 heterozygous mice; and 2) determine the histoarchitectural and transcriptomic alterations of the striatum of these mutants. The proposed exploratory studies will be the first to elucidate the role of protocadherins in TS ontogeny and validate the first model of TS based on a high-risk vulnerability gene. These results are likely to lead to the identification of novel pathogenic processes and specific molecular pathways involved in TS etiology. Our results will lead to future larger studies aimed at the analysis of early neurodevelopmental causes of TS and the design of novel specific pharmacotherapies with better efficacy, tolerability, and safety profiles.
项目摘要/摘要

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 }}

Marco Bortolato其他文献

Marco Bortolato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('Marco Bortolato', 18)}}的其他基金

Mechanisms of information-processing and executive deficits caused by sleep deprivation
睡眠剥夺引起的信息处理和执行缺陷的机制
  • 批准号:
    10886925
  • 财政年份:
    2023
  • 资助金额:
    $ 19.06万
  • 项目类别:
Disentangling the biological links between violence and alcohol use
解开暴力和酗酒之间的生物学联系
  • 批准号:
    10660813
  • 财政年份:
    2023
  • 资助金额:
    $ 19.06万
  • 项目类别:
Exploring the role of neuroactive steroids in Tourette syndrome
探索神经活性类固醇在抽动秽语综合征中的作用
  • 批准号:
    10656348
  • 财政年份:
    2022
  • 资助金额:
    $ 19.06万
  • 项目类别:
Exploring the role of microbiota and inflammation in tic fluctuations
探索微生物群和炎症在抽动波动中的作用
  • 批准号:
    10431544
  • 财政年份:
    2022
  • 资助金额:
    $ 19.06万
  • 项目类别:
Exploring the role of neuroactive steroids in Tourette syndrome
探索神经活性类固醇在抽动秽语综合征中的作用
  • 批准号:
    10464500
  • 财政年份:
    2022
  • 资助金额:
    $ 19.06万
  • 项目类别:
Exploring the role of microbiota and inflammation in tic fluctuations
探索微生物群和炎症在抽动波动中的作用
  • 批准号:
    10612010
  • 财政年份:
    2022
  • 资助金额:
    $ 19.06万
  • 项目类别:
Exploring the role of the protocadherin CELSR3 in Tourette syndrome
探索原钙粘蛋白 CELSR3 在抽动秽语综合征中的作用
  • 批准号:
    10358988
  • 财政年份:
    2021
  • 资助金额:
    $ 19.06万
  • 项目类别:
Exploring steroid-based therapies to reduce opioid abuse
探索基于类固醇的疗法以减少阿片类药物滥用
  • 批准号:
    9916192
  • 财政年份:
    2020
  • 资助金额:
    $ 19.06万
  • 项目类别:
Deciphering gene-environment interactions in pathological reactive aggression
解读病理性反应性攻击中的基因-环境相互作用
  • 批准号:
    10460716
  • 财政年份:
    2014
  • 资助金额:
    $ 19.06万
  • 项目类别:
Deciphering gene-environment interactions in pathological reactive aggression
解读病理性反应性攻击中的基因-环境相互作用
  • 批准号:
    9116021
  • 财政年份:
    2014
  • 资助金额:
    $ 19.06万
  • 项目类别:

相似海外基金

Enhancing Structural Competency in School-Based Health Centers to Address LGBTQ+ Adolescent Health Equity
增强校本健康中心的结构能力,以解决 LGBTQ 青少年健康公平问题
  • 批准号:
    10608426
  • 财政年份:
    2023
  • 资助金额:
    $ 19.06万
  • 项目类别:
Application and feasability of a brief digital screening tool to address parental and adolescent tobacco and electronic cigarette use in pediatric medical care - a pilot study
简短的数字筛查工具的应用和可行性,以解决儿科医疗中父母和青少年烟草和电子烟的使用问题 - 一项试点研究
  • 批准号:
    486580
  • 财政年份:
    2022
  • 资助金额:
    $ 19.06万
  • 项目类别:
    Studentship Programs
Co-design of an intervention to address alcohol use among adolescent boys and young men in Tanzania
共同设计一项干预措施,解决坦桑尼亚青春期男孩和年轻男性的饮酒问题
  • 批准号:
    MR/V032380/1
  • 财政年份:
    2022
  • 资助金额:
    $ 19.06万
  • 项目类别:
    Research Grant
Complex intervention to optimise adolescent BMI pre-conception to address the double burden of malnutrition: A RCT in rural and urban South Africa
优化青少年孕前体重指数以解决营养不良的双重负担的复杂干预措施:南非农村和城市的随机对照试验
  • 批准号:
    MR/V005790/1
  • 财政年份:
    2021
  • 资助金额:
    $ 19.06万
  • 项目类别:
    Research Grant
Application of a brief digital screening tool to address parental and adolescent tobacco and electronic cigarette use in pediatric medical care
应用简短的数字筛查工具来解决儿科医疗中父母和青少年烟草和电子烟的使用问题
  • 批准号:
    455984
  • 财政年份:
    2021
  • 资助金额:
    $ 19.06万
  • 项目类别:
    Operating Grants
Complex intervention to optimise adolescent BMI pre-conception to address the double burden of malnutrition: A RCT in rural and urban South Africa
优化青少年孕前体重指数以解决营养不良的双重负担的复杂干预措施:南非农村和城市的随机对照试验
  • 批准号:
    MR/V005790/2
  • 财政年份:
    2021
  • 资助金额:
    $ 19.06万
  • 项目类别:
    Research Grant
Development of the Cannabis Actions and Practices (CAP): A Parent-Focused Intervention to Address Adolescent Marijuana Use
大麻行动和实践 (CAP) 的发展:以家长为中心的干预措施,解决青少年大麻使用问题
  • 批准号:
    10057761
  • 财政年份:
    2020
  • 资助金额:
    $ 19.06万
  • 项目类别:
Development of the Cannabis Actions and Practices (CAP): A Parent-Focused Intervention to Address Adolescent Marijuana Use
大麻行动和实践 (CAP) 的发展:以家长为中心的干预措施,解决青少年大麻使用问题
  • 批准号:
    10213683
  • 财政年份:
    2020
  • 资助金额:
    $ 19.06万
  • 项目类别:
Targeted interventions to address the multi-level effects of gender-based violence on PrEP uptake and adherence among adolescent girls and young women in Kenya
有针对性的干预措施,以解决性别暴力对肯尼亚少女和年轻妇女接受和坚持 PrEP 的多层面影响
  • 批准号:
    9403567
  • 财政年份:
    2017
  • 资助金额:
    $ 19.06万
  • 项目类别:
Designing targeted interventions to address HIV vulnerabilities and improve clinical outcomes among conflict affected adolescent girls and young women under 25 in Northern Uganda
设计有针对性的干预措施,以解决乌干达北部受冲突影响的少女和 25 岁以下年轻妇女的艾滋病毒脆弱性并改善临床结果
  • 批准号:
    356145
  • 财政年份:
    2016
  • 资助金额:
    $ 19.06万
  • 项目类别:
    Operating Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了