Mechanisms Underlying the Cerebellar Contribution to Autism in Mouse Models of Tu

Tu 小鼠模型中小脑对自闭症的贡献机制

基本信息

  • 批准号:
    8685363
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 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:
    2013-08-01 至 2014-09-05
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Autism is a devastating neurodevelopmental disorder characterized by social impairment, restrictive thinking/repetitive behaviors, and communication impairment presenting before age three. Therapeutic development has been hampered by poor understanding of the underlying pathophysiology. Cerebellar dysfunction has been implicated in autism pathogenesis; however, the precise role for the cerebellum in these disorders remains unclear. Tuberous Sclerosis Complex, a genetic disorder caused by mutation in either Tsc1 or Tsc2, has high rates of autism (~50%). Patients with TSC have significant cerebellar abnormalities, which correlate with the presence of autism in TSC, while functional imaging with cerebellar dysfunction also differentiates TSC patients with autism. To investigate the cerebellar contribution to autistic behaviors, Dr. Tsai generated a mouse model with Tsc1 loss specifically in cerebellar Purkinje cells (PCs). Loss of Tsc1 in PCs was sufficient to generate autistic-like behaviors in mice in addition to abnormal neuronal morphology and impaired electric excitability. As mTOR is elevated with loss of Tsc1, Dr. Tsai treated this model with the mTOR specific inhibitor, rapamycin, which resulted in the prevention of pathological and behavioral abnormalities. These findings lead to the hypothesis that abnormal PC morphology and function contribute to autistic-like phenotypes while also providing the foundation to delineate the neuroanatomical basis and critical periods for development and treatment of autistic-like behaviors. To test these hypotheses, the current mentored training proposal has the following specific aims (1) Determine the molecular and neuroanatomical mechanisms underlying autistic-like behaviors in Purkinje cell-specific Tsc1 mutant mice. (2) Define the critical periods for autistic-like behaviors in Purkinje cell specific Tsc1 mutant mice. (3) Define the cerebellar neuroanatomical underlying autistic-like behaviors. These studies will provide important molecular, behavioral, and neuroanatomical insight into the contribution of cerebellar dysfunction to the pathophysiology of autism while also providing the foundation for rational therapeutic development for these devastating disorders. These studies will be performed under the dual mentorship of Dr. Mustafa Sahin, a pioneer in the understanding of the neurological basis for TSC, and Dr. Wade Regehr, a renowned expert in cerebellar circuitry and physiology. The Department of Neurology will provide a fertile environment to define the cerebellar contribution to autism. Dr. Tsai is a child neurologist who directs the Cerebellar Disorders Clinic at Boston Children's Hospital. His career goal is to become an independent physician-scientist committed to understanding the contribution of cerebellar dysfunction to behavioral, learning, and neurodevelopmental disorders such as autism. This mentored award will provide Dr. Tsai a structured, productive training experience that will bolster his transition to becoming an independent physician-scientist.
描述(由申请人提供):自闭症是一种破坏性的神经发育障碍,其特征是社交障碍,限制性思维/重复行为和沟通障碍,出现在三岁之前。由于对潜在病理生理的理解不足,治疗发展受到阻碍。小脑功能障碍与自闭症的发病机制有关;然而,小脑在这些疾病中的确切作用仍不清楚。结节性硬化症是一种由Tsc1或Tsc2突变引起的遗传性疾病,自闭症的发病率很高(约50%)。TSC患者有明显的小脑异常,这与TSC中是否存在自闭症有关,而伴有小脑功能障碍的功能成像也可以区分TSC患者是否患有自闭症。为了研究小脑对自闭症行为的贡献,蔡博士建立了一个小脑浦肯野细胞(PCs)中Tsc1特异性缺失的小鼠模型。除了神经元形态异常和电兴奋性受损外,PCs中Tsc1的缺失足以在小鼠中产生自闭症样行为。由于mTOR随着Tsc1的缺失而升高,蔡博士用mTOR特异性抑制剂雷帕霉素治疗该模型,从而预防了病理和行为异常。这些发现提出了异常的PC形态和功能有助于自闭症样表型的假设,同时也为描述自闭症样行为发展和治疗的神经解剖学基础和关键时期提供了基础。为了验证这些假设,目前的指导训练方案有以下具体目的:(1)确定浦肯野细胞特异性Tsc1突变小鼠自闭症样行为的分子和神经解剖学机制。(2)明确浦肯野细胞特异性Tsc1突变小鼠自闭症样行为的关键期。(3)定义自闭症样行为的小脑神经解剖学基础。这些研究将为小脑功能障碍对自闭症病理生理的贡献提供重要的分子、行为和神经解剖学的见解,同时也为这些破坏性疾病的合理治疗发展提供基础。这些研究将在Mustafa Sahin博士和Wade Regehr博士的双重指导下进行。Mustafa Sahin博士是了解TSC神经学基础的先驱,Wade Regehr博士是小脑回路和生理学方面的知名专家。神经内科将提供一个丰富的环境来定义小脑对自闭症的贡献。蔡医生是一名儿童神经科医生,负责指导小脑疾病诊所

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)

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Peter T. Tsai其他文献

Author Correction: Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice
作者更正:自闭症中小脑连接的改变以及小脑介导的小鼠自闭症相关行为的拯救
  • DOI:
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    25
  • 作者:
    Catherine J. Stoodley;Anila M. D’Mello;J. Ellegood;V. Jakkamsetti;Pei Liu;M. B. Nebel;Jennifer M. Gibson;Elyza Kelly;Fantao Meng;C. A. Cano;J. Pascual;S. Mostofsky;J. Lerch;Peter T. Tsai
  • 通讯作者:
    Peter T. Tsai
Autism and cerebellar dysfunction: Evidence from animal models.
自闭症和小脑功能障碍:来自动物模型的证据。
Neuronal cell type specific roles for emNprl2/em in neurodevelopmental disorder-relevant behaviors
神经元细胞类型特异性作用于 emNprl2/em 在神经发育障碍相关行为中的作用
  • DOI:
    10.1016/j.nbd.2025.106790
  • 发表时间:
    2025-02-01
  • 期刊:
  • 影响因子:
    5.600
  • 作者:
    Brianne Dentel;Lidiette Angeles-Perez;Abigail Y. Flores;Katherine Lei;Chongyu Ren;Andrea Pineda Sanchez;Peter T. Tsai
  • 通讯作者:
    Peter T. Tsai
Therapeutic Targeting of mTORC2 in mTORopathies
mTORC2 在 mTORopathies 中的治疗靶向
  • DOI:
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    16.2
  • 作者:
    Brianne Dentel;Christine O. Escamilla;Peter T. Tsai
  • 通讯作者:
    Peter T. Tsai
Erythropoietin, Biochemistry of
促红细胞生成素的生物化学
  • DOI:
  • 发表时间:
    2003
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kelly A. Wong;Peter T. Tsai;A. Jegalian;N. Kertesz;Robert A. Lee;Hong Wu
  • 通讯作者:
    Hong Wu

Peter T. Tsai的其他文献

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{{ truncateString('Peter T. Tsai', 18)}}的其他基金

Cerebellum and cerebellar-regulated circuit contribution to Fragile X Syndrome
小脑和小脑调节回路对脆性 X 综合征的影响
  • 批准号:
    10622521
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Cerebellum and cerebellar-regulated circuit contribution to Fragile X Syndrome
小脑和小脑调节回路对脆性 X 综合征的影响
  • 批准号:
    10613700
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Cerebellum and cerebellar-regulated circuit contribution to Fragile X Syndrome -
小脑和小脑调节回路对脆性 X 综合征的影响 -
  • 批准号:
    10346910
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Cerebellum and cerebellar-regulated circuit contribution to Fragile X Syndrome
小脑和小脑调节回路对脆性 X 综合征的影响
  • 批准号:
    10826887
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Cerebellum and cerebellar-regulated circuit contribution to Fragile X Syndrome
小脑和小脑调节回路对脆性 X 综合征的影响
  • 批准号:
    10403964
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Cerebellar-cerebro cortical circuits in ASD
ASD 中的小脑-大脑皮层回路
  • 批准号:
    10056053
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Cerebellum and cerebellar-regulated circuit contribution to Fragile X Syndrome
小脑和小脑调节回路对脆性 X 综合征的影响
  • 批准号:
    10183330
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Cerebellar-cerebro cortical circuits in ASD
ASD 中的小脑-大脑皮层回路
  • 批准号:
    10733753
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Cerebellar-cerebro cortical circuits in ASD
ASD 中的小脑-大脑皮层回路
  • 批准号:
    10055733
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Cerebellar-cerebro cortical circuits in ASD
ASD 中的小脑-大脑皮层回路
  • 批准号:
    10308062
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:

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Accelerated Magnetic Resonance Elastography for Brain Stiffness Analysis in Children with Classic Autistic Disorder
加速磁共振弹性成像用于经典自闭症儿童脑僵硬分析
  • 批准号:
    10223915
  • 财政年份:
    2020
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    --
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加速磁共振弹性成像用于经典自闭症儿童脑僵硬分析
  • 批准号:
    10457950
  • 财政年份:
    2020
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Development of PC driven concept learning and achievement evaluation system for the children with autistic disorder
PC驱动的自闭症儿童概念学习和成绩评估系统的开发
  • 批准号:
    25590285
  • 财政年份:
    2013
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Evaluation of Autistic Disorder using Artificial School Class Game
使用人工学校课堂游戏评估自闭症
  • 批准号:
    23650117
  • 财政年份:
    2011
  • 资助金额:
    --
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    Grant-in-Aid for Challenging Exploratory Research
DENSE MAPPING OF CANDIDATE REGIONS LINKED TO AUTISTIC DISORDER
与自闭症相关的候选区域的密集绘图
  • 批准号:
    8167215
  • 财政年份:
    2010
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DENSE MAPPING OF CANDIDATE REGIONS LINKED TO AUTISTIC DISORDER
与自闭症相关的候选区域的密集绘图
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    7951908
  • 财政年份:
    2009
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    --
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OPEN LABEL RISPERIDONE IN CHILDREN AND ADOLESCENTS WITH AUTISTIC DISORDER
开放标签利培酮用于患有自闭症的儿童和青少年
  • 批准号:
    7953733
  • 财政年份:
    2009
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    --
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DENSE MAPPING OF CANDIDATE REGIONS LINKED TO AUTISTIC DISORDER
与自闭症相关的候选区域的密集绘图
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开发智力低下、自闭症和其他残疾人沟通能力的通用辅助技术设备的研究
  • 批准号:
    19300281
  • 财政年份:
    2007
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    --
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    Grant-in-Aid for Scientific Research (B)
sensorimotor gating processing in autistic disorder ; functional magnetic resonance imaging study
自闭症障碍中的感觉运动门控处理;
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    --
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