Mechanisms of DUX4 mediated FSHD pathology
DUX4 介导的 FSHD 病理机制
基本信息
- 批准号:10554358
- 负责人:
- 金额:$ 60.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-03 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:4q35ASH1L geneAddressAdultAffectAgeAnimal ModelAnimal Muscular DystrophyArtificial Human ChromosomesAutomobile DrivingBiologicalBiological AssayCellsChromatinChromatin Remodeling FactorChromosomesClinicalClustered Regularly Interspaced Short Palindromic RepeatsComplexD4Z4DevelopmentDiseaseDistalEngraftmentEnhancersEpigenetic ProcessFacioscapulohumeral Muscular DystrophyFemaleFundingGene ExpressionGene Expression ProfileGenesGeneticGenomeGoalsHealthHumanMediatingModelingMusMuscleMuscle CellsMuscle DevelopmentMuscle FibersMyoblastsMyopathyNatural regenerationPathogenesisPathogenicityPathologyPathway interactionsPatientsProteinsRegulationRelaxationReporterRepressionRoleSMARCA5 geneSeveritiesSkeletal MuscleSpecificityTestingTherapeuticTherapeutic InterventionTissuesTransgenic OrganismsValidationXenograft procedurecausal variantdiagnostic assayeffective therapyin vivoinsightknock-downmalemouse modelnew therapeutic targetnovelpreventtargeted treatmenttherapeutic developmenttherapeutic targettranslational potentialvirulence gene
项目摘要
SUMMARY
Facioscapulohumeral Muscular Dystrophy (FSHD) is one of the most prevalent myopathies affecting
males and females of all ages, and currently there is no cure or therapeutic intervention available. The
long-term goal of this project is to determine the epigenetic mechanisms leading to pathogenic gene
expression in FSHD, and identify regulatory components that are viable targets for therapeutic
development. FSHD is a complex genetic and epigenetic disease caused by chromatin relaxation of
the D4Z4 macrosatellite repeat array at chromosome 4q35, which leads to aberrant expression of the
DUX4 gene from the distal-most repeat unit. The DUX4 protein, in turn, activates a host of genes
normally expressed in early development, which cause pathology when mis-expressed in adult
skeletal muscle. This established model of FSHD pathogenesis has stimulated the search for DUX4-
based therapeutic targets, including approaches to block DUX4 expression. While normal
mechanisms of D4Z4 repression have been well-characterized, very little is known about the factors
and pathways responsible for facilitating aberrant activation of DUX4. Previously, we showed that the
degree and stability of epigenetic dysregulation at the FSHD-associated 4q35 locus is the key
determinant for DUX4 expression, clinical presentation, and severity of FSHD pathology. Thus,
targeting epigenetic dysregulation in FSHD is a potentially powerful therapeutic avenue. Such an
approach would be greatly aided by a better understanding of the factors facilitating DUX4
expression, each of which represents a potential target for therapeutic inhibition. In a candidate-based
screen, we identified several epigenetic regulators with druggable domains that function as novel
activators of DUX4. Here, we will characterize these epigenetic facilitators of DUX4 expression and
validate their potential as therapeutic targets in FSHD. We will determine the global effects of
reducing the expression of these factors on skeletal muscle health and development using primary
patient cells and novel animal models. Finally, we will test the translational potential of inhibiting these
DUX4 regulators in an FSHD human xenograft mouse model derived from FSHD patient myoblasts
with their endogenous D4Z4 arrays. DUX4 regulators will be inhibited by CRISPR inhibition and
assayed for specificity. Successful completion of this project will provide key insights into the
mechanisms of epigenetic dysregulation in FSHD and validate the translational potential of novel
therapeutic targets in vivo.
概括
面肩肱型肌营养不良症 (FSHD) 是最常见的肌病之一,影响
所有年龄段的男性和女性,目前尚无可用的治愈或治疗干预措施。这
该项目的长期目标是确定导致致病基因的表观遗传机制
FSHD 中的表达,并确定作为治疗可行靶标的调节成分
发展。 FSHD 是一种复杂的遗传和表观遗传疾病,由染色质松弛引起
染色体 4q35 上的 D4Z4 大卫星重复阵列,导致异常表达
来自最远端重复单元的 DUX4 基因。 DUX4 蛋白反过来激活一系列基因
通常在早期发育中表达,当在成人中错误表达时会导致病理
骨骼肌。这种 FSHD 发病机制的建立模型刺激了对 DUX4- 的研究
基于治疗靶点,包括阻断 DUX4 表达的方法。虽然正常
D4Z4 抑制机制已得到充分表征,但对其因素知之甚少
以及负责促进 DUX4 异常激活的途径。之前,我们表明
FSHD 相关 4q35 位点表观遗传失调的程度和稳定性是关键
DUX4 表达、临床表现和 FSHD 病理严重程度的决定因素。因此,
针对 FSHD 的表观遗传失调是一种潜在的强大治疗途径。这样一个
更好地理解促进 DUX4 的因素将大大有助于该方法
表达,每个都代表治疗抑制的潜在靶标。在基于候选人的
筛选后,我们发现了几种具有可药物结构域的表观遗传调节因子,这些调节因子具有新颖的功能
DUX4 的激活剂。在这里,我们将描述 DUX4 表达的这些表观遗传促进因子
验证它们作为 FSHD 治疗靶点的潜力。我们将确定全球影响
使用初级方法减少这些因素对骨骼肌健康和发育的影响
患者细胞和新型动物模型。最后,我们将测试抑制这些的转化潜力
源自 FSHD 患者成肌细胞的 FSHD 人类异种移植小鼠模型中的 DUX4 调节剂
及其内源性 D4Z4 阵列。 DUX4 调节因子将被 CRISPR 抑制所抑制
测定特异性。该项目的成功完成将为我们提供重要的见解
FSHD 表观遗传失调的机制并验证新型药物的转化潜力
体内治疗靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(2)
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Peter L Jones其他文献
Engineered telomeres in transgenic Xenopus laevis
转基因非洲爪蟾的工程端粒
- DOI:
10.1007/s11248-007-9076-0 - 发表时间:
2007 - 期刊:
- 影响因子:3
- 作者:
R. Wuebbles;Peter L Jones - 通讯作者:
Peter L Jones
Purification of MeCP2-containing deacetylase from Xenopus laevis.
从非洲爪蟾中纯化含有 MeCP2 的脱乙酰酶。
- DOI:
10.1385/1-59259-182-5:131 - 发表时间:
2002 - 期刊:
- 影响因子:0
- 作者:
Peter L Jones;P. Wade;A. Wolffe - 通讯作者:
A. Wolffe
Validation of the association between MRI and gene signatures in facioscapulohumeral dystrophy muscle: implications for clinical trial design
面肩肱肌营养不良症 MRI 与基因特征之间关联的验证:对临床试验设计的影响
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
Chao;S. Friedman;L. Snider;S. R. Bennett;T. Jones;Peter L Jones;Dennis Shaw;S. Blemker;Lara I. Riem;Olivia DuCharme;R. Lemmers;S. M. van der Maarel;Leo H. Wang;R. Tawil;J. Statland;S. Tapscott - 通讯作者:
S. Tapscott
Programming the Transcriptional State of Replicating Methylated DNA*
对复制甲基化 DNA 的转录状态进行编程*
- DOI:
10.1074/jbc.m010967200 - 发表时间:
2001 - 期刊:
- 影响因子:0
- 作者:
W. Stünkel;S. Ait;Peter L Jones;A. Wolffe - 通讯作者:
A. Wolffe
Facioscapulohumeral muscular dystrophy region gene 1 (FRG1) is a dynamic RNA-associated and actin bundling protein
面肩肱型肌营养不良症区域基因 1 (FRG1) 是一种动态 RNA 相关和肌动蛋白捆绑蛋白
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
C. Sun;S. Koningsbruggen;Steven W. Long;Kirsten;Straasheijm;R. Klooster;T. Jones;M. Bellini;L. Lévesque;William;M. Brieher;S. M. V. D. Maarel;Peter L Jones - 通讯作者:
Peter L Jones
Peter L Jones的其他文献
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{{ truncateString('Peter L Jones', 18)}}的其他基金
Accessible FSHD diagnostics through epigenetic analysis
通过表观遗传分析进行 FSHD 诊断
- 批准号:
10556422 - 财政年份:2022
- 资助金额:
$ 60.52万 - 项目类别:
Accessible FSHD diagnostics through epigenetic analysis
通过表观遗传分析进行 FSHD 诊断
- 批准号:
10391097 - 财政年份:2022
- 资助金额:
$ 60.52万 - 项目类别:
Mechanisms of DUX4 mediated FSHD pathology
DUX4 介导的 FSHD 病理机制
- 批准号:
9288155 - 财政年份:2017
- 资助金额:
$ 60.52万 - 项目类别:
Mechanisms of DUX4 mediated FSHD pathology
DUX4 介导的 FSHD 病理机制
- 批准号:
9457189 - 财政年份:2017
- 资助金额:
$ 60.52万 - 项目类别:
Pathogenic Mechanisms in Facioscapulohumeral Muscular Dystrophy
面肩肱型肌营养不良症的发病机制
- 批准号:
9277391 - 财政年份:2016
- 资助金额:
$ 60.52万 - 项目类别:
Establishing an FSHD-like mouse for therapeutic development
建立类 FSHD 小鼠用于治疗开发
- 批准号:
9167305 - 财政年份:2016
- 资助金额:
$ 60.52万 - 项目类别:
Mechanisms of DUX4 mediated FSHD pathology
DUX4 介导的 FSHD 病理机制
- 批准号:
8506320 - 财政年份:2013
- 资助金额:
$ 60.52万 - 项目类别:














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