Fragile X Spectrum as Model for Neurogenetic Mechanisms of Cognitive Dysfunction

脆性 X 谱作为认知功能障碍神经发生机制的模型

基本信息

批准号：
8096554
负责人：
TONY J SIMON
金额：
$ 43.19万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8096554
关键词：
Address Adult Age Alleles Area Behavioral Brain CGG repeat Cereals Characteristics Child Childhood Clinical Clinical Trials Cognitive Complement Complex Data Dependence Development Disease Dose FMR1 FMR1 Gene FXTAS Fostering Fragile X Mental Retardation Protein Fragile X Syndrome Future Genes Genetic Image Analysis Impaired cognition Impairment Individual Investigation Longevity Magnetic Resonance Imaging Measures Memory Messenger RNA Methods Mind Modeling Molecular Mutation Neurocognitive Outcome Outcome Measure Parietal Pattern Performance Phase Phenotype Process Production RNA Relative (related person)Structure Testing Therapeutic Variant base cognitive function expectation feeding imaging modality knock-down method development neurochemistry neurogenetics neuromechanism novel protein expression relating to nervous system research study response spatiotemporal tool treatment effect

项目摘要

Fragile X is unique among neurogenetic conditions because it is the only such disorder with a dose-response mechanism based on a single gene (CGG-repeat-dependence of phenotypes). Also, it produces varying outcomes as a result of different pathogenic mechanisms related to FMR1 gene dysregulation - low/absent FMR1 protein (FMRP) in fragile X syndrome; elevated levels of "toxic" FMR1 RNA. As a result of these characteristics, fragile X provides a unique model for developing a "molecules to mind" explanation of a neurogenetic disorder that can then be used to generate hypotheses about the genetic bases of disorders with less clear molecular mechanisms. Thus, the overall objective of this component is to understand how variations in the mutation of a single gene (FMR1) produce a spectrum of cognitive dysfunction in both childhood and adulthood. To this end, we will generate the first detailed neurocognitive profile of an integrated set of cognitive domains that preliminary data suggest are highly vulnerable to changes in the expression of FMRP. The profile will consist of data derived from hypothesis-driven experimental cognitive processing tasks and magnetic resonance imaging (MRI) methods that will produce structural, functional and connectivity measures. We will refer to this profile as the FMR1 Sensitive Neurocognitive Profile (FSNP). It will focus on spatiotemporal, memory, numerical, and executive cognitive functions. It will be characterized in children and adults who have the fragile X full mutation and extended to smaller alleles in the premutation range, and to unaffected (normal repeat) controls. In our investigations we will consider the effect of two continuous variables: FMRP expression level and FMR1 mRNA level, and one categorical variable: phase of development (childhood or adulthood). There will be extensive interaction with other components. With Project 1 we will share the neurocognitive specification of phenotypes that will foster understanding of molecular mechanisms and treatment effects and we will be dependent on their molecular and cellular assessments. With Project 2 there will be a bidirectional feed of behavioral and MRI assessments, especially to drive investigations of the "mixed phenotype" where FMRP and FMR1 RNA changes may interact. Data (and methods) shared between Projects 3 and 4 will extend lifespan analyses, clarify neurochemical mechanisms and neural progressions toward FXTAS, and drive novel MRI analysis method development.

脆性 X 在神经遗传性疾病中是独一无二的，因为它是唯一具有剂量反应的此类疾病基于单个基因的机制（CGG-表型重复依赖性）。此外，它还产生不同的与 FMR1 基因失调相关的不同致病机制导致的结果 - 低/不存在脆性 X 综合征中的 FMR1 蛋白（FMRP）； “有毒”FMR1 RNA 水平升高。由于这些特征，脆弱的 X 提供了一个独特的模型，用于开发“分子思维”解释神经遗传性疾病，然后可用于生成有关疾病遗传基础的假设分子机制不太清楚。因此，该组件的总体目标是了解如何单个基因 (FMR1) 突变的变异会导致两者的一系列认知功能障碍童年和成年。为此，我们将生成第一个详细的神经认知概况初步数据显示，一组综合的认知领域极易受到认知领域变化的影响 FMRP 的表达。该概况将由来自假设驱动的实验认知的数据组成处理任务和磁共振成像（MRI）方法，将产生结构、功能和连通性措施。我们将此配置文件称为 FMR1 敏感神经认知配置文件 (FSNP)。它将重点关注时空、记忆、数字和执行认知功能。其特点将是具有脆弱 X 完全突变并在前突变中扩展到较小等位基因的儿童和成人范围，以及不受影响（正常重复）的对照。在我们的调查中，我们将考虑两个因素的影响连续变量：FMRP 表达水平和 FMR1 mRNA 水平，以及一个分类变量：发展（童年或成年）。与其他组件将会有广泛的交互。和项目 1 我们将分享表型的神经认知规范，这将促进对分子机制和治疗效果，我们将依赖于它们的分子和细胞评估。项目 2 将提供行为和 MRI 评估的双向反馈，尤其是推动对 FMRP 和 FMR1 RNA 变化可能相互作用的“混合表型”的研究。数据项目 3 和项目 4 之间共享的（和方法）将延长寿命分析，阐明神经化学 FXTAS 的机制和神经进展，并推动新型 MRI 分析方法的开发。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adult Female Fragile X Premutation Carriers Exhibit Age- and CGG Repeat Length-Related Impairments on an Attentionally Based Enumeration Task.

DOI：
10.3389/fnhum.2011.00063
发表时间：
2011-01-01
期刊：
Frontiers in human neuroscience
影响因子：
2.9
作者：
Goodrich-Hunsaker, Naomi J;Wong, Ling M;Simon, Tony J
通讯作者：
Simon, Tony J

Enhanced manual and oral motor reaction time in young adult female fragile X premutation carriers.

DOI：
10.1017/s1355617711000634
发表时间：
2011-07
期刊：
JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY
影响因子：
2.6
作者：
Goodrich-Hunsaker, Naomi J.;Wong, Ling M.;McLennan, Yingratana;Tassone, Flora;Harvey, Danielle;Rivera, Susan M.;Simon, Tony J.
通讯作者：
Simon, Tony J.

Altered structural brain connectome in young adult fragile X premutation carriers.

DOI：
10.1002/hbm.22491
发表时间：
2014-09
期刊：
HUMAN BRAIN MAPPING
影响因子：
4.8
作者：
Leow, Alex;Harvey, Danielle;Goodrich-Hunsaker, Naomi J.;Gadelkarim, Johnson;Kumar, Anand;Zhan, Liang;Rivera, Susan M.;Simon, Tony J.
通讯作者：
Simon, Tony J.

Young adult female fragile X premutation carriers show age- and genetically-modulated cognitive impairments.

DOI：
10.1016/j.bandc.2011.01.001
发表时间：
2011-04
期刊：
BRAIN AND COGNITION
影响因子：
2.5
作者：
Goodrich-Hunsaker, Naomi J.;Wong, Ling M.;McLennan, Yingratana;Srivastava, Siddharth;Tassone, Flora;Harvey, Danielle;Rivera, Susan M.;Simon, Tony J.
通讯作者：
Simon, Tony J.

Temporal dynamics of attentional selection in adult male carriers of the fragile X premutation allele and adult controls.