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: 9318277
• 负责人: JOHN N. CONSTANTINO
• 金额: $ 129.19万
• 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 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9318277
• 关键词: Affect; Animal Model; Award; Behavior; Behavioral; Biological Markers; Biological Models; Brain; Caliber; Cell model; Cells; Child; Clinical; Clinical Sciences; Clinical assessments; Collection; Core Facility; Data; Derivation procedure; Development; Developmental Disabilities; Early Intervention; Environment; Epigenetic Process; Etiology; Family; Female; Fostering; Generations; Genetic; Genetic Predisposition to Disease; Genomic approach; Genomics; Goals; Human; Image; Individual; Inherited; Intellectual functioning disability; Interruption; Intervention; Knowledge; Mental Retardation and Developmental Disabilities Research Centers; Molecular; Nature; Neurodevelopmental Disability; Neurology; Newborn Infant; Pathogenesis; Pathogenicity; Patients; Phenotype; Population; Population Attributable Risks; Predisposition; Prevention; Preventive Intervention; Process; Psychiatry; Research; Research Personnel; Research Project Grants; Resources; Risk; Science; Scientific Advances and Accomplishments; Structure; Synapses; Syndrome; Translating; Translational Research; Translations; Universities; Variant; Washington; autism spectrum disorder; brain behavior; cognitive neuroscience; design; developmental disease; effective intervention; frontier; functional genomics; human subject; indexing; innovation; medical schools; neuroimaging; next generation; novel; premature; prenatal; prevent; programs; public health relevance; relating to nervous system; resilience; sex; treatment response; white matter injury

 DESCRIPTION (provided by applicant): The last decade of research in intellectual and developmental disabilities (IDD) has been notably characterized by rapid advances in understanding the nature and complexity of inherited susceptibilities to IDD, but genetic discovery has not yet fulfilled the promise of more effective intervention, even for monogenic IDD syndromes. It is the immediate priority of a next generation of research to capitalize upon knowledge about causation in IDD (both genetic and environmental) and translate it into higher-impact intervention for as many individuals and families affected as possible. In the second cycle of the IDDRC at Washington University in St. Louis (IDDRC@WUSTL), our strategy for contributing to this effort preserves our Center's original focus on characterization of white matter injury to the newborn brain, but extends the scope of Core activity to facilitate a comprehensive approach to understanding and preventing developmental disorders of neural connectivity at the respective levels of cell, synapse, circuit, and behavior, and brings on line major strengths of WUSTL in genomics, behavioral/cognitive neuroscience, and clinical-translational science. The overarching goals of our Center are as follows: (1) To facilitate high-caliber, translational research on the pathogenesis and treatment of IDDs by sustaining an innovative Core structure that attracts and supports qualified, collaborative investigators, and interacts synergistically with complementary Core facilities of other U.S. IDDRCs. We propose to support an Administrative Core, a Developmental Neuroimaging Core, a Model Systems Core (encompassing capacity and expertise for both animal and cellular models of IDD), and a Clinical Translational Core. (2) To cultivate nodes of interdisciplinary scientific activity in frotiers of IDD research which are critical for the derivation of higher-impact treatment and preventive intervention, across 4 major themes: (i) The prevention of prematurity and its neurodevelopmental consequences; (ii) The elucidation of robust intermediate DD phenotypes (as markers of pathogenic processes, targets of early intervention, and indices of response to treatment); (iii) In-depth characterization of the developing human brain, and (iv) Functional genomic approaches to elucidating convergent mechanisms of IDD pathogenesis. (3) To conduct a signature research project that represents a bold, critical step toward higher-impact intervention for IDD, capitalizes upon both the Core structure of our IDDRC and institutional strengths at WUSTL, and epitomizes the manner in which our IDDRC facilitates trans-disciplinary research. Our project is designed to elucidate mechanisms of sex-specific modulation-of-expression of inherited risk for autism spectrum disorders, at the respective levels of cell, brain, and behavior. A goal is to identify compensatory mechanisms underlying resilience among females in ASD-affected families, for the purpose of recapitulating those mechanisms in novel interventions which would be of major relevance to a large proportion of the population of individuals at risk or affected by familial autistic syndromes.

 描述(申请人提供)：过去十年对智力和发育障碍(IDD)的研究的显著特点是，在理解IDD遗传易感性的性质和复杂性方面取得了快速进展，但基因发现尚未实现更有效的干预承诺，即使是对单基因IDD综合征也是如此。下一代研究的当务之急是利用有关IDD(遗传和环境)因果关系的知识，并将其转化为对尽可能多受影响的个人和家庭采取更有效的干预措施。在圣路易斯华盛顿大学IDDRC(IDDRC@WUSTL)的第二个周期中，我们为这项工作做出贡献的战略保持了我们中心最初对新生儿大脑白质损伤特征的关注，但扩展了核心活动的范围，以促进在细胞、突触、回路和行为水平上了解和预防神经连接发育障碍的综合方法，并发挥WUSTL在基因组学、行为/认知神经科学和临床翻译科学方面的主要优势。我们中心的总体目标如下：(1)通过保持创新的核心结构，吸引和支持合格的协作研究人员，并与美国其他IDDRC的补充核心设施协同互动，促进对IDDS发病机制和治疗的高水平转化性研究。我们建议支持一个管理核心、一个发育神经成像核心、一个模型系统核心(包括IDD动物和细胞模型的能力和专业知识)和一个临床翻译核心。(2)在IDD研究的各个阶段培养跨学科的科学活动节点，这对产生更有效的治疗和预防干预至关重要，涉及四个主要主题：(I)预防早产及其神经发育后果；(Ii)阐明强健的中间DD表型(作为致病过程的标志、早期干预的目标和治疗反应的指标)；(Iii)深入描述发育中的人脑；以及(Iv)用功能基因组方法阐明IDD发病机制的趋同机制。(3)开展一个标志性的研究项目，代表着向更高影响力的IDD干预迈出的大胆而关键的一步，利用我们IDDRC的核心结构和WUSTL的机构优势，并集中体现我们的IDDRC促进跨学科研究的方式。我们的项目旨在阐明自闭症谱系障碍遗传风险的性别特异性表达调节机制，分别在细胞、大脑和行为水平上。一个目标是确定受自闭症影响的家庭中女性潜在的恢复力补偿机制，目的是在新的干预措施中总结这些机制，这些干预措施将与大部分面临自闭症风险或受家族性自闭症综合征影响的个人人口具有重大相关性。