Modifiers of FMR1-associated Disorders: Application of High Throughput Technologi

FMR1 相关疾病的修饰剂：高通量技术的应用

• 批准号: 8793381
• 负责人: Stephen T. Warren
• 金额: $ 180.69万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793381
• 关键词: Address; Affect; Age; Area; Bioinformatics; Biological Assay; Biological Markers; Candidate Disease Gene; Cardiovascular Diseases; Cerebellar Gait; Clinical assessments; Communities; Disease; Drosophila genus; Dysautonomias; Ensure; Environment; Epilepsy; Estrogens; Executive Dysfunction; Exposure to; F7 gene; FMR1; FMR1 repeat; FMRP; FXTAS; Faculty; Family; Fostering; Fracture; Fragile X Syndrome; Functional disorder; Gene-Modified; Genes; Genetic; Genetic Epistasis; Genome; Genomics; Goals; Health; Human Genetics; Hypogonadism; Impaired cognition; Infertility; Institution; Intention Tremor; Knowledge; Lead; Menstruation; Messenger RNA; Modeling; Mutation; Neurobiology; Neurodegenerative Disorders; Neuropathy; Osteoporosis; Ovarian; Parkinsonian Disorders; Pathway interactions; Penetrance; Phenotype; Population Genetics; Premature Ovarian Failure; Prevalence; Recording of previous events; Research; Research Personnel; Research Project Grants; Resource Sharing; Sampling Studies; Scientist; Series; Severities; Students; System; Tail; Technology; Training; Translating; Tremor/Ataxia Syndrome; Turner' s Syndrome; Universities; Variant; Woman; Work; aged; base; boys; case control; clinically significant; experience; genetic variant; genome sequencing; high throughput technology; innovation; insight; male; medical schools; men; next generation; novel; novel strategies; outcome forecast

DESCRIPTION (provided by applicant): The goals of our Center, "Modifiers of FMR1-associated disorders: application of high throughput technologies", are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMR1- associated conditions. Project A will focus on the variable expression of epilepsy among boys with Fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of Fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the permutation (PM), with a lifetime prevalence of 30% among males. Project C focuses Fragile X association primary ovarian insufficiency (FXPOI), which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. POF leads to infertility and estrogen-deficiency related disorders usually reserved for the aged. Our goal is to identify and understand the extent of the epistemic effects of modifying genes on these three Mendelian disorders. The Center will include three projects and two shared cores, all administered by an Administrative Core. Each proposed research project will take the same novel approach to define a set of candidate genes for further study in mammalian systems. They will: 1) use the Recruitment Core B to ascertain the 100 cases and 100 controls drawn from extreme phenotypic tails of each disorder, 2) conduct whole genome sequencing on each of the 100/100 cases/controls series using the expertise and experience of the Genomics and Analytical Core C, and 3) after validating variants, assess the function of prioritized genes using the established phenotypic assays in the corresponding Drosophila models. The research we propose in our Center is highly innovative, using cutting-edge technologies, to answer fundamental questions related to Fragile X-related disorders. All Center investigators are part of Emory University, an institution with possibly the largest group of independent faculty working on Fragile X-related disorders and with nearly a 30-year history of contributions to the field. Moreover, an added synergy and excitement within this Center is driven by the common theme among all the projects, ensuring a highly interactive and productive research environment.

描述（由申请人提供）：我们中心的目标“FMR1 相关疾病的调节剂：高通量技术的应用”针对 RFA 研究领域，以促进对 FMR1 相关病症的病理生理学的理解。这三个研究项目的拟议目标的完成将导致确定 FMR1 相关病症的可变表达性或不完全外显率的遗传基础。 A 项目将重点关注患有脆性 X 综合征 (FXS) 的男孩中癫痫的变异表达，这是一种在 15% 受影响的男孩中发生的共病，我们推测基因组中其他地方的变异是造成这种情况的原因。同样，项目 B 将重点关注男性脆性 X 震颤/共济失调综合征 (FXTAS) 的不完全外显率，这是一种排列 (PM) 人群中的神经退行性疾病，男性终生患病率为 30%。项目 C 重点关注脆性 X 相关原发性卵巢功能不全 (FXPOI)，20% 的 PM 携带者表现为卵巢早衰 (POF)，或 40 岁之前月经停止。POF 会导致不孕症和通常保留的雌激素缺乏相关疾病对于老年人来说。我们的目标是确定和理解基因修饰对这三种孟德尔疾病的认知影响程度。该中心将包括三个项目和两个共享核心，全部由行政核心管理。每个拟议的研究项目都将采用相同的新颖方法来定义一组候选基因，以便在哺乳动物系统中进一步研究。他们将：1) 使用招募核心 B 确定从每种疾病的极端表型尾部抽取的 100 个病例和 100 个对照，2) 利用以下人员的专业知识和经验对 100/100 例/对照系列中的每一个进行全基因组测序基因组学和分析核心 C，以及 3) 验证变异后，使用相应果蝇中已建立的表型测定来评估优先基因的功能模型。我们中心提出的研究具有高度创新性，利用尖端技术来回答与脆性 X 相关疾病相关的基本问题。所有中心研究人员均来自埃默里大学，该大学可能拥有最大的从事脆性 X 相关疾病研究的独立教职人员群体，并在该领域拥有近 30 年的贡献历史。此外，所有项目的共同主题推动了该中心的协同作用和兴奋感，确保了高度互动和富有成效的研究环境。