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: 9069622
• 负责人: Stephen T. Warren
• 金额: $ 191.2万
• 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 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069622
• 关键词: Address; Affect; Age; Area; Bioinformatics; Biological Assay; Biological Markers; Candidate Disease Gene; Cardiovascular Diseases; Cerebellar Gait; Clinical assessments; Communities; Comorbidity; 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 Gene; Fragile X Syndrome; Functional disorder; Genes; Genetic; Genetic Epistasis; Genome; Genomics; Goals; Human Genetics; Hypogonadism; Impaired cognition; Impairment; Infertility; Institution; Intention Tremor; Knowledge; Lead; Mendelian disorder; 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; Recruitment Activity; Research; Research Personnel; Research Project Grants; Resource Sharing; Sampling Studies; Scientist; Series; Severities; Students; Syndrome; System; Tail; Technology; Training; Translating; Tremor/Ataxia Syndrome; Universities; Variant; Woman; aged; 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; primary ovarian insufficiency; public health relevance; synergism; whole genome

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）：我们中心的目标是“ FMR1相关疾病的修饰符：高吞吐技术的应用”，针对RFA研究领域，以促进对FMR1相关疾病的病理生理学的理解。从三个研究项目中完成的目标的完成将导致鉴定出可变表达性或FMR1相关条件的不完全渗透率的遗传基础。项目A将重点关注脆弱X综合征（FXS）的男孩中癫痫的可变表达，这是一种在15％受影响男孩中发生的合并症，我们推测基因组中其他地方的变异是造成的。同样，项目B将集中在男性中脆弱的X震颤/共济失调综合征（FXTA）的不完全渗透性上，这是男性的神经退行性疾病（PM）的神经退行性疾病，男性终生患病率为30％。 Project C将脆弱的X关联焦点卵巢不足（FXPOI）聚焦，该卵巢不足（FXPOI）在20％的PM携带者中表现为早产卵巢衰竭（POF），或者在40岁之前停止月经。POF会导致不孕症和雌激素缺乏障碍相关的疾病，通常为年龄保留。我们的目标是识别和理解修饰基因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。每个提出的研究项目将采用相同的新方法来定义一组候选基因，以在哺乳动物系统中进行进一步研究。他们将：1）使用招聘核心B来确定每个疾病的极端表型尾部绘制的100例和100个对照，2）使用基因组学和分析核心C的专业知识和经验进行整个基因组测序，并在验证变体中使用验证的基因效应，使用基因组和分析核心C的专业知识和经验进行了分析核心C，以及3）。我们在中心提出的研究具有高度创新性，使用尖端技术，以回答与脆弱的X相关疾病有关的基本问题。所有中心调查人员都是埃默里大学（Emory University）的一部分，埃默里大学（Emory University）可能是最大的独立教师，从事脆弱的X相关疾病，并拥有将近30年的对该领域的贡献。此外，该中心内部的增强协同作用和兴奋是由所有项目之间的共同主题驱动的，从而确保了高度互动和生产性的研究环境。