Washington University Intellectual and Developmental Disabilities Research Center

总体项目摘要 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了解、改善和/或预防 神经发育障碍，通过转化科学研究在各自的细胞水平， 突触，电路和行为，利用WUSTL在基因组学，行为/认知 神经科学和临床转化科学。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，这些设施在科学和技术领域占据关键地位， 社区，吸引和支持高素质的研究人员，并促进高素质的转化研究 IDDs的发病机制和治疗。在此应用程序中，我们提出了具体的增强，我们的每一个 科学核心设施：一个扩大的技术团队，为发展神经影像核心，一个专门的 模型系统核心内的细胞模型单元（与跨IDDRC工作组校准的方法， IDDRC@WUSTL共同领导的IDD细胞模型），以及一个新的临床试验/自然史研究单位 临床转化核心（CTC）。反恐委员会将继续协助收集和解释 跨代的基因组、表型、环境和生物标志物数据，并逐步促进 将关于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。的 IDDRC@WUSTL将为研究工作提供关键基础设施，这些研究工作与其他研究机构产生了协同作用。 校内和校外中心/研究所，包括一项新资助的对出生在 对于参加March of Dimes早产儿研究中心队列的母亲， 自闭症婴儿脑成像研究（IBIS）的复制队列，唐氏综合征的两个多站点倡议， 以及美国国立卫生研究院自闭症基因发现卓越网络中心。(2)培育新的节点 中心内的跨学科科学活动，在碘缺乏病研究的前沿，这是至关重要的派生 沿着中心的四大主题：（一）预防 早产及其神经发育后果;（ii）鉴定中间表型， IDD的发展;（iii）发育中的人脑的结构和功能表征，以及（iv） 与IDD发病机制相关的功能基因组学。在这个周期中，我们将在先前成功培养 一个活跃、互动和富有成效的从事缺碘症科学的科学家社区，挑战自己， 产生和利用新知识，促进治疗和预防方面的转化进展。(3)到 开展一个标志性的研究项目，这是朝着更高影响力的干预迈出的大胆的关键一步， 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几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相关基因的单倍不足，以确定IDD的收敛机制。

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.