Fragile X Premutations, Mechanisms and Modifiers

脆性 X 前突变、机制和修饰因子

基本信息

批准号：
10271291
负责人：
David Loren Nelson
金额：
$ 180万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-25 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10271291
关键词：
5&apos Untranslated Regions Address Age Antisense Oligonucleotides Area Base Sequence Bioinformatics Biological Models CGG repeat CGG repeat expansion Chromosome Fragile Sites Clinical Collection Coupled DNA Data Development Disease Epigenetic Process FMR1 FMRP FXTAS Family Fragile X Gene Fragile X Premutation Fragile X Syndrome Functional disorder Gene-Modified Genetic Genetic Transcription Genomics Haplotypes Human Impairment Individual Lead Mammals Mediating Modeling Neurologic Neurons Onset of illness Ovarian Pathogenicity Patients Penetrance Pharmacologic Substance Process Production Proteins RNA Reproductive Biology Research Research Personnel Resources Role Running Series Severities Structure Symptoms Toxic effect Translations Variant Work cohesion effective therapy gain of function genome wide screen human disease improved insight multidisciplinary novel primary ovarian insufficiency reproductive risk prediction risk variant targeted treatment therapeutic development therapeutic target therapy development tool

项目摘要

Fragile X Premutations- Mechanisms and Modifiers Fragile X-associated disorders are a heterogeneous group of conditions arising from alterations in the size, content, and epigenetic state of a polymorphic CGG repeat within the FMR1 gene. Described as the first repeat expansion disorder nearly 30 years ago, FMR1 CGG repeat expansions are both an important cause of neurological, reproductive and neurodevelopmental disease as well as an archetype for understanding repeat expansions and the mechanisms by which they elicit dysfunction. Work over past decades delineated the native functions of the fragile X protein, FMRP, and the consequences of its loss and the explored toxic gain-of function mechanisms (RNA-mediated toxicity via protein sequestration, and protein mediated toxicity from Repeat associated non-AUG (RAN) translation) elicited by transcribed CGG repeats. Despite these efforts, we still lack effective therapies for any of the cardinal Fragile X- associated disorders. Here we propose a paradigm shift in our approach to FX associated disorders. Rather than focusing solely on specific diseases (Fragile X Syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI)), the Center structure enables us to directly engage the mechanistic cross-talk between conditions and between the FMR1 locus and related repeat expansion disorders. Our central hypothesis is that a deeper understanding of genetic factors which underlie clinical disease onset and penetrance in premutation associated disorders and an exploration of native CGG repeat functions will reveal novel insights into both how repeats cause disease and how they might be targeted therapeutically. Led by a multidisciplinary team featuring many leaders in the Fragile X field, we will address this hypothesis in three cohesive projects all focused on premutation disorders by using data-driven genomic and bioinformatics approaches coupled with emerging tools and integrative model systems. By pooling our substantial data, expertise and resources, we will pursue a deeper understanding of FX premutation pathogenic mechanisms and define a series of robust and viable targets for therapeutic development across Fragile X-associated disorders.

脆弱 X 前突变 - 机制和修饰符脆性 X 相关疾病是由基因改变引起的一组异质性疾病 FMR1 基因内多态性 CGG 重复的大小、内容和表观遗传状态。 FMR1 CGG 重复被描述为近 30 年前第一个重复扩展障碍扩张是神经、生殖和神经发育的重要原因疾病以及理解重复扩张和机制的原型它们会引起功能障碍。过去几十年的工作描述了脆性 X 蛋白、FMRP 及其丢失的后果和探索的毒性增益功能机制（RNA介导的通过蛋白质隔离的毒性，以及蛋白质介导的毒性）由转录的 CGG 引起的重复相关非 AUG (RAN) 翻译的毒性重复。尽管做出了这些努力，我们仍然缺乏针对任何主要脆性 X- 相关疾病。在这里，我们建议对外汇相关疾病的治疗方法进行范式转变。而不是仅关注特定疾病（脆性 X 综合征 (FXS)、脆性 X 相关疾病震颤/共济失调综合征 (FXTAS) 和脆性 X 相关原发性卵巢功能不全（FXPOI）），中心结构使我们能够直接参与之间的机械串扰 FMR1 基因座之间的条件以及相关的重复扩展障碍。我们的中央假设是对临床疾病背后的遗传因素有更深入的了解前突变相关疾病的发病率和外显率以及天然 CGG 的探索重复功能将揭示重复如何引起疾病以及它们如何引起疾病的新见解可能会成为治疗的目标。由多学科团队领导，其中包括许多领域的领导者脆弱的 X 场，我们将在三个有凝聚力的项目中解决这个假设，所有项目都专注于通过使用数据驱动的基因组和生物信息学方法耦合前突变疾病具有新兴工具和集成模型系统。通过汇集我们的大量数据、专业知识和资源，我们将追求对 FX 前突变致病性的更深入了解机制并确定一系列稳健且可行的治疗开发目标脆性 X 相关疾病。