NEUROPSYCHIATRIC/MOLECULAR ASSOCIATION IN FRAGILE X

FMR1全突变女孩的焦虑，避免和唤醒的发育轨迹

ALLAN REISS (1993-05-01 to 2002-04-30) $12,541,889

Project ID: R01MH050047 (NIMH)

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Abstract

DESCRIPTION (Adapted from applicant's abstract): Fragile X (fra X) syndrome, the most common heritable cause of neuropsychiatric disability, is caused by mutations of the FMRI gene. Our previous research showed that individuals with fra X manifest a characteristic set of maladaptive behaviors, and a particular profile of cognitive strengths and weaknesses. Initial studies of genetic and environmental correlates of the fra X neuropsychiatric profile further suggest (1) an association between FMRI activation and specific domains of cognitive function and, (2) that the profile and magnitude of environmental influences on neurobehavioral outcome may be altered in children with fra X compared to non-fra X controls. Particular brain regions also are morphologically abnormal in persons with fra X; of particular note are findings of aberrant volume, and indirect evidence of abnormal function of the hippocampus and amygdala. Combined with data indicating that hyperarousal, social anxiety and visual-spatial deficits are key components of the fra X phenotype, and pilot data indicating abnormal cortisol secretion in affected individuals, these findings suggest dysfunction of limbic-hypothalamic-pituitary-adrenal (HPA) systems in this condition. The overarching goal of our newly proposed studies is to expand our knowledge of the association of specific genetic, environmental, neuroendocrine and neuroanatomical factors with neuropsychiatric outcome in children with fra X. To accomplish this goal, three specific aims are identified. In the first aim, we will enhance our understanding of the relation between specific genetic and environmental factors and cognitive and behavioral outcome in children with fra X. In the second aim, we will measure the function and reactivity of the HPA axis in this same population. These two aims will be accomplished with in-home evaluation of 150 children with fra X and 150 unaffected siblings. In the third aim, we will utilize structural and functional brain imaging in individuals with fra X to identify the specific neurofunctional systems underlying cognitive and behavioral abnormalities. This last aim will be achieved using structural and functional MRI, and FDG-PET studies. The information gained from this work will contribute to our understanding of the complex interplay among gene state, brain function, hormonal milieu and environmental influences in fra X. The proposed studies are especially designed to provide practical information regarding neurobiological, hormonal and environmental factors that may be directly amenable to intervention. Study of this important single gene condition also will contribute to our fundamental knowledge of linkages among gene, environment, brain, and behavior in children.

脆性X综合征（FraX）是遗传性精神障碍最常见的已知病因。 FMR1基因突变是FraX的原因，导致FMR1蛋白（FMRP）的表达降低，并增加了认知，行为和情绪功能障碍特定特征的风险。由于这些特征与重要（特发性）DSM-IV诊断的相似性，FraX对个体的研究为自闭症，社交恐惧症，抑郁症和认知障碍等疾病提供了一个理解窗口。 FraX的研究也是跨越多个临床和基础科学领域实现创新跨学科研究的门户。这种研究提供了新的见解，了解遗传和环境因素如何有助于典型和非典型人类行为的复杂变化。在这个应用中，我们描述了自1992年以来一直存在的FraX个人独特研究的计划。在我们研究的第一个组成部分中，我们将继续对FraX达到的80位熟练人物进行纵向研究发展的关键阶段 - 青春期和青春期。将收集关键认知，行为，神经内分泌，遗传和环境数据，并对这些数据与功能结局的关系进行检验。这项研究的这一部分将代表青春期和年轻成年期间FraX队列的最大的综合性前瞻性调查。在我们研究的第二部分，我们将使用新的行为学研究和先进的多模态神经影像学实验来扩展我们对FraX的神经生物学的调查，以更充分地阐明大脑结构，生物化学，连通性和功能的异常认知和行为。在第二个目标的范围内，我们还将研究简要干预试验的功效，重点是改善执行机能和社会行为。这些试点试验将利用创新的行为和实时功能磁共振成像（rtfMRI）策略，旨在产生初步数据，以指导未来新型FraX特异性治疗的发展。由PI执行的跨学科脑科学研究中心（CIBSR），Allan Reiss博士代表了世界上少数几个对FraX进行全面，跨学科研究的承诺。 CIBSR的工作特别侧重于应用调查，将提供新的知识，方法和工具来改善FraX及其家属的生活。