Washington University Intellectual and Developmental Disabilities Research Center-Administrative Down Syndrome Supplement

华盛顿大学智力与发育障碍研究中心-行政唐氏综合症补充品

• 批准号: 9934527
• 负责人: JOHN N. CONSTANTINO
• 金额: $ 56.91万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-18 至 2020-07-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9934527
• 关键词: Address; Affect; Benchmarking; Biological; Cell model; Characteristics; Chemicals; Cognitive; Cognitive deficits; Collaborations; Communities; Data; Data Analyses; Defect; Down Syndrome; Functional disorder; Future; Genetic; Grant; Human; Individual; Intellectual functioning disability; Interneurons; Intervention; Lead; Link; Mental Retardation and Developmental Disabilities Research Centers; Meta-Analysis; Methods; Modeling; Molecular; Molecular Abnormality; Molecular Profiling; Molecular Target; Neurons; Parents; Pathogenicity; Pathway interactions; Patients; Phenotype; Population; Process; Public Health; Reproducibility; Research; Research Personnel; Research Project Grants; Resource Sharing; Resources; Site; Therapeutic Intervention; Universities; Washington; Work; base; cognitive ability; cognitive function; data warehouse; design; developmental disease; developmental genetics; experimental study; functional genomics; induced pluripotent stem cell; insight; patient population; phenotypic data; screening; therapeutic target; transcriptomics

ABSTRACT Down syndrome (DS, trisomy 21) is the most common genetic cause of intellectual and developmental disability (IDD), but the cellular and molecular abnormalities that contribute to specific cognitive deficits are not well defined. Although DS individuals all have the same genetic cause of intellectual disability (trisomy 21), there is considerable variability in cognitive function across the patient population. In addition, while decades of data indicate that cortical interneurons are a vulnerable neuronal population in human DS and that their perturbation may be linked to altered cognitive function in DS patients, there is very limited data regarding how altered interneuron characteristics and dysfunction contribute to DS. Here, to address these challenges, we propose to build patient-derived induced pluripotent stem cell (iPSC) models from deeply phenotyped DS individuals who have been stratified based on cognitive ability (Aim 1). These models will provide a valuable resource for the DS research community, and will be used for cross-site replication of phenotypes and data meta-analyses conducted by the Cellular Modeling Units of two Intellectual and Developmental Disabilities Research Centers (IDDRCs), enhancing rigor and reproducibility of IDD cellular modeling across the network. In Aims 2 and 3, we will identify cellular and molecular signatures that reflect differences in cognitive ability: interneurons differentiated from these DS patient iPSCs will be analyzed for specific cellular defects, as well as through exploratory transcriptomic analysis, to identify cellular phenotypes and molecular signatures that distinguish DS individuals with high versus low cognitive functioning. Results from these experiments will define patient-relevant contributors to affectation that can be exploited in future projects to identify potential therapeutic targets for DS. This work integrates major directives of the IDDRC@WUSTL parent U54 grant in elucidation of intermediate phenotypes for IDDs, functional genomic discovery of convergent pathogenic mechanisms, and building of capacity for cellular modeling of IDDs, both at the IDDRC@WUSTL and throughout the IDDRC network. This collaboration also contributes to ongoing cross-IDDRC initiatives, led by these co-Investigators, to build shared cellular modeling resources for IDD research, including cross-IDDRC calibrated methods and benchmarks, new IDD models, and IDDRC-supported bio- and data-repositories for IDD cellular models. These initiatives will build capacity for IDD resource sharing and meta-analysis of data among IDDRC investigators throughout the network, enhancing the impact of this and other research projects, and will facilitate identification of convergent intermediate phenotypes, pathways, and molecular targets across different IDD models. These models provide a renewable, sharable resource, whereby the altered processes, pathways, and targets that are identified in this project can serve as a basis for future work using these models in combination with chemical and molecular screening to identify potential interventions.

抽象的 唐氏综合症（DS，21 三体）是智力和发育障碍最常见的遗传原因 残疾（IDD），但导致特定认知缺陷的细胞和分子异常并不 定义明确。尽管 DS 个体都具有相同的智力障碍遗传原因（21 三体）， 患者群体的认知功能存在相当大的差异。此外，虽然几十年来 数据表明，皮质中间神经元是人类 DS 中的脆弱神经元群体，并且它们的 扰动可能与 DS 患者的认知功能改变有关，但关于如何影响认知功能的数据非常有限 中间神经元特征的改变和功能障碍会导致 DS。在这里，为了应对这些挑战，我们 提议从深度表型 DS 构建患者来源的诱导多能干细胞 (iPSC) 模型 根据认知能力进行分层的个体（目标 1）。这些模型将提供有价值的 DS 研究社区的资源，将用于表型和数据的跨站点复制 由细胞建模单位对两种智力和发育障碍进行的荟萃分析 研究中心 (IDDRC)，增强整个网络中 IDD 细胞建模的严谨性和可重复性。 在目标 2 和 3 中，我们将识别反映认知能力差异的细胞和分子特征： 将分析从这些 DS 患者 iPSC 分化而来的中间神经元的特定细胞缺陷，以及 通过探索性转录组分析，识别细胞表型和分子特征 区分具有高认知功能和低认知功能的 DS 个体。这些实验的结果将 定义与患者相关的影响因素，可以在未来的项目中利用这些因素来识别潜在的影响 DS 的治疗靶点。 这项工作整合了 IDDRC@WUSTL 母公司 U54 赠款的主要指令，以阐明 IDD 的中间表型、趋同致病机制的功能基因组发现，以及 在 IDDRC@WUSTL 和整个 IDDRC 内开展 IDD 细胞建模能力建设 网络。这项合作还有助于由这些联合研究者领导的持续的跨 IDDRC 举措， 为 IDD 研究构建共享细胞建模资源，包括跨 IDDRC 校准方法和 基准、新的 IDD 模型以及 IDDRC 支持的 IDD 细胞模型生物和数据存储库。 这些举措将建设 IDDRC 之间 IDD 资源共享和数据元分析的能力 整个网络的研究人员，增强本研究项目和其他研究项目的影响，并将 促进收敛的中间表型、途径和分子靶点的识别 不同的 IDD 型号。这些模型提供了可再生、可共享的资源，通过改变流程， 该项目中确定的途径和目标可以作为使用这些模型的未来工作的基础 结合化学和分子筛选来确定潜在的干预措施。

项目成果

Neural plasticity across the lifespan.

• DOI: 10.1002/wdev.216
• 发表时间: 2017-01
• 期刊: WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY
• 作者: Power, Jonathan D.;Schlaggar, Bradley L.
• 通讯作者: Schlaggar, Bradley L.

Resting state signal latency predicts laterality in pediatric medically refractory temporal lobe epilepsy.

• DOI: 10.1007/s00381-018-3770-5
• 发表时间: 2018-05
• 期刊: Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery
• 作者: Shah MN;Mitra A;Goyal MS;Snyder AZ;Zhang J;Shimony JS;Limbrick DD;Raichle ME;Smyth MD
• 通讯作者: Smyth MD

Deconstructing autism: from unitary syndrome to contributory developmental endophenotypes.

• DOI: 10.1080/09540261.2018.1433133
• 发表时间: 2018-03
• 期刊: International review of psychiatry (Abingdon, England)
• 作者: Constantino JN

Changes of White Matter Diffusion Anisotropy in Response to a 6-Week iPad Application-Based Occupational Therapy Intervention in Children with Surgically Treated Hydrocephalus: A Pilot Study.

对接受手术治疗的脑积水儿童进行为期 6 周的基于 iPad 应用的职业治疗干预后白质扩散各向异性的变化：一项试点研究。

• DOI: 10.1055/s-0036-1584938
• 发表时间: 2016
• 期刊: Neuropediatrics
• 影响因子: 1.4
• 作者: Yuan,Weihong;Harpster,Karen;Jones,BlaiseV;Shimony,JoshuaS;McKinstry,RobertC;Weckherlin,Nicole;Powell,StephanieS;Barnard,Holly;Engsberg,Jack;Kadis,DarrenS;Dodd,Jonathan;Altaye,Mekibib;Limbrick,DavidD;Holland,ScottK;Simpso
• 通讯作者: Simpso

Autism-Related Variation in Reciprocal Social Behavior: A Longitudinal Study.

• DOI: 10.1111/cdev.13170
• 发表时间: 2019-03
• 期刊: Child development
• 影响因子: 4.6
• 作者: Wagner RE;Zhang Y;Gray T;Abbacchi A;Cormier D;Todorov A;Constantino JN
• 通讯作者: Constantino JN