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: 10224301
• 负责人: JOHN N. CONSTANTINO
• 金额: $ 126万
• 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/10224301
• 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; 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; preventive intervention; 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.

总体项目摘要 对于华盛顿大学智力和发展障碍研究中心的第三个周期， 我们提出了理解、改善和/或预防的综合方法的下一阶段 神经发育障碍通过在各自的细胞水平上进行翻译科学研究， 突触、回路和行为，充分利用WUSTL在基因组学、行为/认知方面的主要优势 神经科学和临床翻译科学。我们中心的总体目标如下：(1) 维持和发展核心科学设施的综合结构，这些设施在科学研究中占据关键的利基地位 社区，吸引和支持高素质的调查人员，并促进高水平的翻译研究 关于IDDS的发病机制和治疗。在此应用程序中，我们建议对我们的每个 科学核心设施：发展神经成像核心的扩大技术团队，致力于 模型系统核心内的细胞模型单元(通过跨IDDRC工作组校准的方法 IDDRC@WUSTL共同领导的IDD细胞模型)和一个新的临床试验/自然史研究单位 在临床翻译核心(CTC)内。反恐委员会将继续协助收集和解释 跨越几代人的基因组、表型、环境和生物标志物数据，并逐步促进 将风险和发病机制方面的新发现转化为对患者影响更大的干预措施。这个 IDDRC@WUSTL将为研究工作提供关键的基础设施，这些工作已经与其他 墙内和墙外中心/研究所，包括一项新资助的对出生婴儿的深入纵向研究 向参加3月迪梅斯早产儿研究中心队列的母亲们，推出一项 自闭症婴儿脑成像研究(IBIS)的复制队列，唐氏综合症的两个多点倡议， 以及美国国立卫生研究院自闭症基因发现卓越网络。(二)培育新经济新节点 中心内的跨学科科学活动，在IDD研究的前沿领域，这对派生至关重要 该中心的四大主题是：(一)预防 早产及其神经发育后果；(Ii)早产儿中间表型的鉴定 IDD的发展；(Iii)发育中人脑的结构和功能特征；和(Iv) 与IDD发病机制相关的功能基因组学。在这个周期中，我们将在以前成功的基础上培养一个 致力于IDD科学的动态、互动和富有成效的科学家社区，挑战自己 产生和利用新知识，以促进治疗和预防方面的翻译性进展。(3)至 实施标志性研究项目，代表着朝着更高影响力的干预迈出的大胆、关键的一步 IDD。在这个项目中，一个新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等基因细胞系中实施，每个细胞系代表 在不同的高置信度IDD相关基因中发现单倍性不足，以确定IDD的收敛机制。