Natural history of individuals with autism spectrum disorder and germline PTEN mutations
患有自闭症谱系障碍和种系 PTEN 突变的个体的自然史
基本信息
- 批准号:10701741
- 负责人:
- 金额:$ 34.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-20 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AdolescentAdultAgeBehaviorBehavioralBehavioral SymptomsBiochemicalBiological MarkersBrainCaringCell ProliferationCharacteristicsChildClinical TrialsCognitionCognitiveComprehensive Health CareConsensusConsensus DevelopmentDataData CollectionDevelopmentEducationElectroencephalographyEtiologyEvaluationFRAP1 geneFunctional disorderFundingFutureGenesGeneticGenetic Predisposition to DiseaseGenetic studyGenomicsGoalsGuidelinesHeritabilityHeterogeneityHeterozygoteHumanIndividualIntervention StudiesKnockout MiceMalignant NeoplasmsMedicalMegalencephalyModelingMolecularMutationNational Comprehensive Cancer NetworkNatural HistoryNeurocognitiveNeurodevelopmental DisorderNeuronsOutcomePI3K/AKTPTEN Hamartoma Tumor SyndromePTEN autism spectrum disorderPTEN genePathway interactionsPatternPeripheralPhenotypePhosphoric Monoester HydrolasesPractice GuidelinesProcessProteinsRecommendationRisk ManagementSeriesSigns and SymptomsSpecificityStratificationSubgroupSymptomsSystemTumor Suppressor ProteinsValidationVariantagedautism spectrum disorderbiomarker identificationbiomarker validationcancer riskcell growthcognitive functioncohortdifferential expressionfrontal lobeindividuals with autism spectrum disordermolecular markermouse modelneuralneural correlateneurobehaviorneurobehavioralneuropathologyneurophysiologyneuropsychiatric disorderpotential biomarkerprecision geneticspsychologicrecruitrepetitive behaviorrisk stratificationsocial communicationspecific biomarkerstherapeutic targettranscriptometreatment planningwhite matter
项目摘要
Autism spectrum disorders (ASD) are an etiologically heterogeneous set of neurodevelopmental disorders
marked by social communication/interaction deficits and restricted/repetitive behaviors. Genetic studies have
identified a strong heritable component, yet >80% of ASD remains idiopathic. Marked heterogeneity has slowed
attempts to identify pathophysiology and related therapeutic targets. One promising strategy to reduce
complexity is to focus on subgroups with a specific genetic etiology, such as ASD associated with germline
heterozygous PTEN mutations (PTEN-ASD, who are always macrocephalic). In the last 4 years, we
characterized cross-sectional neurobehavioral and neurocognitive differences among PTEN-ASD, those with
PTEN mutations but no ASD (PTEN-no ASD) and macrocephalic ASD without PTEN mutations (Macro-ASD)
and begun longitudinal data collection in individuals aged 3-21. We propose a natural history study of the
neurophenotypic and molecular characteristics of PTEN-ASD with the goals of understanding risk management
and treatment planning as well as identifying sensitive biomarkers for intervention studies. We will recruit 170
(70 from current cohort) individuals with PTEN-ASD, Macro-ASD, and PTEN no-ASD, and expanding recruitment
to aged 18 months to 45 years. Data collected will include: (a) cancer occurrence, (b) autism and other behavioral
symptoms, (c) neurocognitive profiles, (d) adaptive function, (e) genomic modifiers, (f) protein levels from
PI3K/AKT/mTOR/S6K pathway, and (g) EEG, in order to: (Aim 1) Determine cross-sectional and longitudinal
neurobehavioral and medical differences between PTEN-ASD and other groups in an expanded age range. This
aim seeks to describe initial levels and longitudinal changes in cancer occurrence, behavioral signs/symptoms,
and cognitive function in PTEN-ASD; (Aim 2) Identify EEG and molecular biomarkers specific to PTEN-ASD and
those shared with other groups. This aim seeks to identify biomarkers that may be treatment targets in
intervention studies; and (Aim 3) Develop a comprehensive, multi-level, longitudinal model of PTEN-ASD to
inform future clinical trials and the development of consensus care guidelines. We will use data from Aims 1 and
2 and from TSC Associated Neuropsychiatric Disorders (TAND) Checklist (after validation). This first
comprehensive longitudinal evaluation of the phenotypic and molecular characteristics of PTEN ASD, to identify
specific molecular pathway and correlated neural abnormalities responsible for ASD symptoms in these
individuals, which can be ably compared to TSC and PMS. It is a crucial next step toward the development of
personalized genetic treatment approaches for PTEN-ASD. Prior to initiating further clinical trials, it will be critical
to identify treatment targets at the molecular, neurophysiological, and behavioral levels.
自闭症谱系障碍(ASD)是一种病因异质性的神经发育障碍
以社交/互动缺陷和限制/重复行为为特征。遗传学研究
虽然确定了一个很强的遗传成分,但>80%的ASD仍然是特发性的。显著的异质性已经减缓
试图确定病理生理学和相关的治疗目标。一个有希望的战略,
复杂性在于关注具有特定遗传病因的亚组,例如与生殖细胞相关的ASD
杂合子PTEN突变(PTEN-ASD,总是大头)。在过去的四年里,我们
PTEN-ASD之间的特征性横截面神经行为和神经认知差异,
PTEN突变但无ASD(PTEN-no ASD)和无PTEN突变的大头ASD(Macro-ASD)
并开始在3-21岁的个体中进行纵向数据收集。我们提出了一个自然历史研究的
PTEN-ASD的神经表型和分子特征,目的是了解风险管理
和治疗计划,以及为干预研究确定敏感的生物标志物。我们将招募170名
(70来自当前队列)患有PTEN-ASD、Macro-ASD和PTENno-ASD的个体,并扩大招募
18个月至45岁。收集的数据将包括:(a)癌症发生率,(B)自闭症和其他行为
症状,(c)神经认知概况,(d)适应功能,(e)基因组修饰剂,(f)来自
PI 3 K/AKT/mTOR/S6 K通路,和(g)EEG,以便:
PTEN-ASD和其他年龄组之间的神经行为和医学差异。这
aim旨在描述癌症发生,行为体征/症状,
(目的2)鉴定PTEN-ASD特异性的EEG和分子生物标志物,
与其他群体共享的。这一目标旨在鉴定可能是治疗靶点的生物标志物,
干预研究;和(目标3)开发一个全面的,多层次的,纵向的PTEN-ASD模型,
为未来的临床试验和共识护理指南的制定提供信息。我们将使用目标1和
2和TSC相关神经精神障碍(TAND)检查表(验证后)。该第一
对PTEN ASD的表型和分子特征进行全面的纵向评价,以鉴定
这些患者中负责ASD症状的特定分子途径和相关神经异常
个人,这可以巧妙地比较TSC和PMS。这是发展的关键一步,
PTEN-ASD的个性化基因治疗方法。在开始进一步的临床试验之前,
在分子、神经生理学和行为水平上确定治疗目标。
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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Charis Eng其他文献
Charis Eng的其他文献
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{{ truncateString('Charis Eng', 18)}}的其他基金
The 6th Annual International PTEN Symposium: From Patient-Centered Research to Clinical Care
第六届国际 PTEN 研讨会:从以患者为中心的研究到临床护理
- 批准号:
10683454 - 财政年份:2023
- 资助金额:
$ 34.94万 - 项目类别:
Modeling Autism and Comorbid Cancer Risk in Individuals with Germline PTEN Mutations
种系 PTEN 突变个体的自闭症和共病癌症风险建模
- 批准号:
10704496 - 财政年份:2022
- 资助金额:
$ 34.94万 - 项目类别:
Modeling Autism and Comorbid Cancer Risk in Individuals with Germline PTEN Mutations
种系 PTEN 突变个体的自闭症和共病癌症风险建模
- 批准号:
10358435 - 财政年份:2022
- 资助金额:
$ 34.94万 - 项目类别:
Natural history of individuals with autism spectrum disorder and germline PTEN mutations
患有自闭症谱系障碍和种系 PTEN 突变的个体的自然史
- 批准号:
10242080 - 财政年份:2014
- 资助金额:
$ 34.94万 - 项目类别:
Deep Sequencing Instrumentation Upgrade - Illumina HiSeq2500
深度测序仪器升级 - Illumina HiSeq2500
- 批准号:
8640603 - 财政年份:2014
- 资助金额:
$ 34.94万 - 项目类别:
Metagenomic profiling of oral polymicrobial flora in head and neck cancers
头颈癌口腔多微生物菌群的宏基因组分析
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8142045 - 财政年份:2010
- 资助金额:
$ 34.94万 - 项目类别:
Genetic Alterations that Initiate Follicular Thyroid Carcinogenesis
引发滤泡性甲状腺癌的基因改变
- 批准号:
8505981 - 财政年份:2008
- 资助金额:
$ 34.94万 - 项目类别:
Genetic Alterations that Initiate Follicular Thyroid Carcinogenesis
引发滤泡性甲状腺癌的基因改变
- 批准号:
8697754 - 财政年份:2008
- 资助金额:
$ 34.94万 - 项目类别:
Genetic Alterations that Initiate Follicular Thyroid Carcinogenesis
引发滤泡性甲状腺癌的基因改变
- 批准号:
9041528 - 财政年份:2008
- 资助金额:
$ 34.94万 - 项目类别:
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