Washington University Intellectual and Developmental Disabilities Research Center

华盛顿大学智力与发育障碍研究中心

• 批准号: 10085124
• 负责人: JOHN N. CONSTANTINO
• 金额: $ 124.46万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-28 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10085124
• 关键词: Affect; Animal Model; Behavior; Behavioral; Biocompatible Materials; Bioinformatics; Biological Markers; Biological Models; Brain; Brain imaging; Caliber; Cell Line; Cell model; Cells; Child; Clinical; Clinical Trials; Collection; Communities; Core Facility; Data; Data Set; Derivation procedure; Development; Developmental Disabilities; Disease; Down Syndrome; Electronic Health Record; Enrollment; Equipment and supply inventories; Etiology; Extramural Activities; Faculty; Familial disease; Family; Functional disorder; Funding; Gene Dosage; Generations; Genes; Genetic; Genomics; Goals; Human; Image; Individual; Infant; Infrastructure; Institutes; Institution; Intellectual and Developmental Disabilities Research Centers; Intellectual functioning disability; Interruption; Intervention; Investigation; Knowledge; Longitudinal Studies; Methods; Molecular; Mothers; Mutation; Natural History; Neurodevelopmental Disability; Neurosciences; Pathogenesis; Pathway interactions; Patients; Phase; Phenotype; Population; Prevention; Preventive Intervention; Quality of life; Registries; Research; Research Infrastructure; Research Personnel; Research Project Grants; Resources; Risk; Rodent Model; Science; Scientist; Specialized Center; Standardization; Structure; Synapses; Syndrome; Therapeutic; To specify; Translating; Translational Research; Translations; United States National Institutes of Health; Universities; Variant; Washington; autism spectrum disorder; base; behavioral genomics; behavioral phenotyping; cognitive neuroscience; cohort; follow-up; frontier; functional genomics; gene discovery; genetic variant; imaging study; medical schools; multiple omics; neuroimaging; new therapeutic target; novel; novel therapeutics; patient population; premature; prevent; programs; prospective; psychosocial; relating to nervous system; success; synergism; working group

Overall Project Abstract For the third cycle of the Intellectual and Developmental Disabilities Research Center at Washington University, we propose a next phase in a comprehensive approach to understanding, ameliorating, and/or preventing neurodevelopmental disability through translational scientific investigation at the respective levels of cell, synapse, circuit, and behavior, capitalizing upon major strengths of WUSTL in genomics, behavioral/cognitive neuroscience, and clinical-translational science. The overarching goals of our Center are as follows: (1) To sustain and evolve an integrated structure of core scientific facilities that occupy a critical niche in the scientific community, attract and support highly-qualified investigators, and facilitate high-caliber, translational research on the pathogenesis and treatment of IDDs. In this application we propose specific enhancements to each of our scientific core facilities: an expanded technical team for the Developmental Neuroimaging Core, a dedicated cellular models unit within the Model Systems Core (methods calibrated with a cross-IDDRC working group for cellular models of IDD co-led by the IDDRC@WUSTL), and a new clinical trials / natural history studies unit within the Clinical-Translational Core (CTC). The CTC will continue to facilitate the collection and interpretation of genomic, phenotypic, environmental and biomarker data across generations, and promote step-wise translation of new discoveries on risk and pathogenesis to higher-impact interventions for patients. The IDDRC@WUSTL will provide critical infrastructure for research efforts that have created synergies with other intramural and extramural Centers/Institutes, including a newly-funded in-depth longitudinal study of infants born to mothers enrolled in the March of Dimes Prematurity Research Center Cohort, the launch of a prospective replication cohort for the Infant Brain Imaging Study of Autism (IBIS), two multisite initiatives in Down Syndrome, and an NIH Autism Center of Excellence Network in gene discovery. (2) To cultivate nodes of new interdisciplinary scientific activity within the Center, in frontiers of IDD research which are critical for the derivation of higher-impact treatment and preventive intervention, along the Center’s four major themes: (i) the prevention of prematurity and its neurodevelopmental consequences; (ii) the identification of intermediate phenotypes in the development of IDD; (iii) structural and functional characterization of the developing human brain, and (iv) functional genomics relevant to IDD pathogenesis. In this cycle we will build on prior successes in cultivating a dynamic, interactive, and productive community of scientists engaged in IDD-science, challenging itself to generate and harness new knowledge toward translational advances in therapeutics and prevention. (3) To conduct a signature research project that represents a bold, critical step toward higher-impact intervention for IDD. In this project, a novel platform for standardizing multi-omic characterization of the consequences of variation in gene dosage will be implemented across dozens of isogenic cell lines, each representing haploinsufficiency in a different high-confidence IDD-related gene, to identify convergent mechanisms of IDD.

项目总体摘要 对于华盛顿大学智力和发育障碍研究中心的第三个周期， 我们建议下一阶段采取全面的方法来理解、改善和/或预防 通过在各个细胞水平进行转化科学研究来发现神经发育障碍， 突触、电路和行为，利用 WUSTL 在基因组学、行为/认知方面的主要优势 我们中心的总体目标如下：（1） 维持和发展在科学领域占据关键地位的核心科学设施的综合结构 社区，吸引和支持高素质的研究人员，并促进高水平的转化研究 在此应用程序中，我们针对 IDD 的发病机制和治疗提出了具体的改进建议。 科学核心设施：发育神经影像核心的扩大技术团队、专门的 模型系统核心内的蜂窝模型单元（通过跨 IDDRC 工作组校准的方法 由 IDDRC@WUSTL 共同领导的 IDD 细胞模型，以及一个新的临床试验/自然历史研究单位 在临床转化核心 (CTC) 内，CTC 将继续促进收集和解释。 跨代的基因组、表型、环境和生物标志物数据，并逐步促进 将风险和发病机制的新发现转化为对患者影响更大的干预措施。 IDDRC@WUSTL 将为与其他研究机构产生协同效应的研究工作提供关键基础设施 校内和校外中心/研究所，包括新资助的对出生婴儿的深入纵向研究 对于参加“March of Dimes”早产儿研究中心队列的母亲来说，推出了一项前瞻性研究 自闭症婴儿脑成像研究 (IBIS) 的复制队列，这是唐氏综合症的两个多站点倡议， 和 NIH 自闭症卓越中心网络的基因发现 (2) 培育新的节点。 中心内的跨学科科学活动，在 IDD 研究的前沿，这对于推导至关重要 围绕中心的四大主题，开展更具影响力的治疗和预防性干预：(i) 预防 (ii) 中间表型的鉴定 IDD 的发展；(iii) 人类大脑发育的结构和功能特征，以及 (iv) 与 IDD 发病机制相关的功能基因组学 在这个周期中，我们将建立在先前成功的基础上。 由从事 IDD 科学的科学家组成的动态、互动和富有成效的社区，挑战自我 产生并利用新知识来推动治疗和预防方面的转化进步 (3) 。 开展一项标志性研究项目，该项目代表着朝着更具影响力的干预措施迈出的大胆而关键的一步 在这个项目中，一个新颖的平台用于标准化多组学表征的后果。 基因剂量的变化将在数十个同基因细胞系中实施，每个细胞系代表 不同高置信度 IDD 相关基因的单倍体不足，以确定 IDD 的收敛机制。