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:10451592
- 负责人:
- 金额:$ 180万
- 依托单位:
- 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:
- 关键词:5&apos Untranslated RegionsAddressAgeAntisense OligonucleotidesAreaBase SequenceBioinformaticsBiological ModelsCGG repeatCGG repeat expansionClinicalCollectionCoupledDNADataDevelopmentDiseaseEpigenetic ProcessFMR1FMRPFXTASFamilyFragile X GeneFragile X PremutationFragile X SyndromeFunctional disorderGene-ModifiedGeneticGenetic TranscriptionGenomicsHaplotypesHumanImpairmentIndividualLeadMammalsMediatingModelingNeurologicNeuronsOnset of illnessOvarianPathogenicityPatientsPenetrancePharmacologic SubstanceProcessProductionProteinsRNAReproductive BiologyResearchResearch PersonnelResourcesRoleRunningSeriesSeveritiesSiteStructureSymptomsToxic effectTranslationsVariantWorkcohesioneffective therapygain of functiongenome wide screenhuman diseaseimprovedinsightmultidisciplinarynovelprimary ovarian insufficiencyreproductiverisk predictionrisk varianttargeted treatmenttherapeutic developmenttherapeutic targettherapy developmenttool
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.
脆性X前突变-机制和修饰
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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专利数量(0)
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David Loren Nelson其他文献
David Loren Nelson的其他文献
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{{ truncateString('David Loren Nelson', 18)}}的其他基金
Baylor College of Medicine Intellectual and Developmental Disabilities Research Center
贝勒医学院智力与发育障碍研究中心
- 批准号:
10221022 - 财政年份:2020
- 资助金额:
$ 180万 - 项目类别:
Baylor College of Medicine Intellectual and Developmental Disabilities Research Center
贝勒医学院智力与发育障碍研究中心
- 批准号:
10085940 - 财政年份:2020
- 资助金额:
$ 180万 - 项目类别:
Fragile X Premutations, Mechanisms and Modifiers
脆性 X 前突变、机制和修饰因子
- 批准号:
10669025 - 财政年份:2020
- 资助金额:
$ 180万 - 项目类别:
Fragile X Premutations, Mechanisms and Modifiers
脆性 X 前突变、机制和修饰因子
- 批准号:
10271291 - 财政年份:2020
- 资助金额:
$ 180万 - 项目类别:
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