KPTN Loss and Megalencephaly: mTOR Activation as Therapeutic Target

KPTN 丢失和巨脑畸形:mTOR 激活作为治疗靶点

基本信息

  • 批准号:
    10544536
  • 负责人:
  • 金额:
    $ 36.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-01-01 至 2025-12-31
  • 项目状态:
    未结题

项目摘要

Mutations in select mTOR pathway genes (MPG) are associated with megalencephaly (ME) and/or hemimegalencephaly (HME) including MTOR (Smith-Kingsmore syndrome, ME), STRADA (Pretzel syndrome, ME), PI3KCA (ME/HME), AKT3 (HME), PTEN (ME), DEPDC5 (HME) and RHEB (HME). Autosomal recessive germline variants in KPTN (kaptin; 19q13.32), part of the mTOR regulatory KICSTOR complex, have been recently identified in a clinical syndrome characterized by ME, intellectual disability, autism, and severe epilepsy (Baple et al., 2014) among the Old Order Amish communities in Ohio and Pennsylvania and more recently outside of the Plain Communities. There are 8 established pathogenic KPTN variants (loss of function) all linked to the clinical syndrome Megalencephaly, Autism, Seizures Developmental Delay (KPTN/MASD). The neurological phenotype includes hypotonia in infancy, autism spectrum disorder, intellectual disability (mild to severe), and seizures (onset between 3 months-27 years). Seizures are typically refractory to standard medical treatments and not amenable to resective surgery). ME is a universal feature of KPTN/MASD by adulthood (orbitofrontal head circumference [OFC] >2 standard deviations for age, with OFC measurements up to 5.4 SDS). Strikingly, serial OFC measurements available from 31 children, revealed that OFC is typically within normal limits at birth, with a rapid increase in OFC within the first 2 years of life with ~75% of patients with OFC >2 SDS by that age. Neuroimaging in a limited number of cases revealed a globally enlarged but structurally normal brain. A Kptn -/- mouse strain was recently developed and now is under investigation in our lab. Amazingly, Kptn-/- mice, but not Kptn +/- mice, also exhibit a ME phenotype with post-natal brain overgrowth, thus mirroring the clinical KPTN/MASD phenotype. This application proposes 3 Aims to investigate the mouse and human KPTN/MASD phenotypes. In Aim 1, we will define the effects of Kptn CRISPR/Cas9 KO in vitro on mTOR pathway activation, cell morphology, and cell motility and effects of mTOR pathway inhibitors (mTORi) in murine neural progenitor cells and neurons. In Aim 2, we will analyze the Kptn -/- brain including histopathology, mTOR signaling activation, and hyperexcitability (EEG), and response to mTORi. In Aim 3 we will define the neurological phenotype of KPTN/MASD in an existing and prospectively collected cohort of individuals within the Plain Community and in the general population. Because of the close phenotypic overlap between the Kptn -/- mouse model and human KPTN/MASD, these studies provide a unique opportunity to set the stage for an interventional clinical trial in KPTN/MASD to prevent brain overgrowth.
选择mTOR通路基因(MPG)的突变与巨脑畸形(ME)和/或

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 }}

Peter B Crino其他文献

Peter B Crino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('Peter B Crino', 18)}}的其他基金

Somatic Mutation in Intractable Focal Epilepsy
难治性局灶性癫痫的体细胞突变
  • 批准号:
    10788846
  • 财政年份:
    2023
  • 资助金额:
    $ 36.33万
  • 项目类别:
KPTN Loss and Megalencephaly: mTOR Activation as Therapeutic Target
KPTN 丢失和巨脑畸形:mTOR 激活作为治疗靶点
  • 批准号:
    10375917
  • 财政年份:
    2022
  • 资助金额:
    $ 36.33万
  • 项目类别:
Somatic Mutation in Intractable Focal Epilepsy
难治性局灶性癫痫的体细胞突变
  • 批准号:
    10662245
  • 财政年份:
    2020
  • 资助金额:
    $ 36.33万
  • 项目类别:
Somatic Mutation in Intractable Focal Epilepsy
难治性局灶性癫痫的体细胞突变
  • 批准号:
    10888458
  • 财政年份:
    2020
  • 资助金额:
    $ 36.33万
  • 项目类别:
Defining disease mechanisms in SLC35A2 epilepsy
定义 SLC35A2 癫痫的疾病机制
  • 批准号:
    10058871
  • 财政年份:
    2020
  • 资助金额:
    $ 36.33万
  • 项目类别:
Defining disease mechanisms in SLC35A2 epilepsy
定义 SLC35A2 癫痫的疾病机制
  • 批准号:
    10609847
  • 财政年份:
    2020
  • 资助金额:
    $ 36.33万
  • 项目类别:
Defining disease mechanisms in SLC35A2 epilepsy
定义 SLC35A2 癫痫的疾病机制
  • 批准号:
    10191063
  • 财政年份:
    2020
  • 资助金额:
    $ 36.33万
  • 项目类别:
Defining disease mechanisms in SLC35A2 epilepsy
定义 SLC35A2 癫痫的疾病机制
  • 批准号:
    10379373
  • 财政年份:
    2020
  • 资助金额:
    $ 36.33万
  • 项目类别:
Somatic Mutation in Intractable Focal Epilepsy
难治性局灶性癫痫的体细胞突变
  • 批准号:
    10453576
  • 财政年份:
    2020
  • 资助金额:
    $ 36.33万
  • 项目类别:
Somatic Mutation in Intractable Focal Epilepsy
难治性局灶性癫痫的体细胞突变
  • 批准号:
    10063291
  • 财政年份:
    2020
  • 资助金额:
    $ 36.33万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了