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
- 来源:
- 关键词:19q13.32AKT3 geneAbnormal CellAdultAffectAgeAmazeAmino AcidsAmishBiological AssayBiological ModelsBirthBrainBrain imagingCRISPR/Cas technologyCaringCell ProliferationCell SizeCellular MorphologyChildClinicClinicalClinical DataClinical TrialsCollaborationsCommunitiesComplexDataDatabasesDedicationsDevelopmentDevelopmental Delay DisordersDiagnosticElectroencephalographyEnrollmentEpilepsyExhibitsFRAP1 geneFamilyGeneral PopulationGenesGenomeGenotypeGerm-Line MutationGrowthHead circumferenceHistopathologyHospitalsHumanIn VitroIndividualIntellectual functioning disabilityInternationalInterventionInvestigationLaboratoriesLifeLinkMagnetic Resonance ImagingMeasurementMedicalMedicineMegalencephalyModelingMouse StrainsMusMuscle hypotoniaMutationNeurologicNeuronsNeuropsychological TestsOhioOperative Surgical ProceduresPTEN geneParentsPathogenicityPathway interactionsPatientsPennsylvaniaPhenotypePlant LeavesPlayPolyhydramnios, megalencephaly, and symptomatic epilepsyPopulationProliferatingRefractoryRegistriesResearchRoleRunningSeizuresSignal TransductionSirolimusSpecialistSyndromeThickVariantautism spectrum disorderautosomebrain overgrowthbrain sizecell motilityclinical centercohortcollegeepileptiformhemimegalencephalyin vivoin vivo Modelinfancyinhibitorloss of functionmTOR inhibitionmouse modelnerve stem cellneuroimagingneuropathologynon-verbalpostnatalpreventprospectiveprotein complexresponsetherapeutic target
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)
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科研奖励数量(0)
会议论文数量(0)
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Peter B Crino其他文献
Peter B Crino的其他文献
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{{ 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:














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