Establishing an FSHD-like mouse for therapeutic development
建立类 FSHD 小鼠用于治疗开发
基本信息
- 批准号:9167305
- 负责人:
- 金额:$ 1.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2016-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAlternative SplicingAnimal ModelApoptosisBindingBiological MarkersBreathingCanis familiarisCharacteristicsChildChromatin StructureClinicalComb animal structureD4Z4DNADNA BindingDNA MethylationDNA-Binding ProteinsDataDevelopmentDiseaseDisease ProgressionElementsEngineeringEnvironmental Risk FactorEpigenetic ProcessEventExhibitsFacioscapulohumeral Muscular DystrophyFemaleFunctional disorderGene ExpressionGene Expression ProfileGene Expression ProfilingGene StructureGenerationsGenesGeneticGenetic RecombinationGoalsHairHand StrengthHistopathologyHomeodomain ProteinsHormonesHumanIn VitroInflammatory ResponseLeadLifeLive BirthMediatingMediator of activation proteinMessenger RNAModelingMolecular ProfilingMusMuscleMuscle WeaknessMuscle functionMuscular DystrophiesMyopathyNonsense-Mediated DecayOxidative StressPathologyPathway interactionsPatientsPhenotypePreclinical TestingProteinsRNA SplicingRegulationResourcesRunningSeveritiesSkeletal MuscleStem cellsTamoxifenTestisTherapeuticTransgenic MiceWNT Signaling PathwayWalkingWheelchairsbasecareercytotoxicitydesignepigenetic regulationexhausthistone modificationmalemodel developmentmouse modelmulticatalytic endopeptidase complexmuscle strengthmuscular dystrophy mouse modelmyogenesispathogenic isoformpreventprotein aggregationrepairedresearch clinical testingtargeted treatmenttherapeutic developmenttherapeutic targettooltranscription factor
项目摘要
PROJECT SUMMARY
Facioscapulohumeral muscular dystrophy (FSHD) is the most prevalent myopathy afflicting males and
females, children and adults. In the majority of clinical FSHD cases, muscle weakness is not
noticeable until the second or third decade of life followed by a progressive pathology impacting many
facets of everyday life, ranging from being unable to comb ones own hair or walk the dog to including
having to change or abandon careers, loss of independence and, in ~20% of FSHD patients,
becoming wheelchair bound an/or require aid in breathing. Currently there are no treatments to
slow down, stop, or reverse disease progression. A major impediment to developing ameliorative
treatments is the lack of a reliable phenotypic FSHD-like animal model based on expression of the DUX4
gene, widely considered the key mediator of FSHD pathophysiology. This project directly addresses this
void. In FSHD, increased expression of DUX4-fl, which can function as a DNA-binding transcription
factor, alters the gene expression profiles of muscles and initiates a cascade of events ultimately leading
to FSHD pathophysiology. Thus, the DUX4-fl mRNA, DUX4- FL protein and downstream targets are all
excellent targets for therapeutic development. For this project, we have successfully engineered a line
of transgenic mice that contains the human DUX4- fl gene maintaining its native gene structure. These
mice are validated to express correctly spliced DUX4-fl mRNA upon Cre-mediated recombination and
develop an aberrant muscle phenotype when DUX4-fl is expressed in developing muscle. This
data strongly supports the ultimate generation of an FSHD-like model mouse; however, the precise
expression conditions that will result in a useful FSHD-like phenotype are still not known. Here, we
will use a commercially available line of mice expressing tamoxifen-inducible Cre in skeletal muscles to
determine the conditions required to generate reproducible FSHD-like phenotypes over a range of
severities. A successful FSHD-like mouse will appear initially healthy, then develop a progressive
myopathic phenotype based on quantifiable metrics of muscle strength and function including grip
strength, rotarod, and the maximum distance each is capable of running before becoming exhausted.
The phenotypes will be confirmed by FSHD-like gene expression analysis and histopathology.
Completion of this project will provide the FSHD field with valuable tools for better understanding
FSHD pathogenic progression and mechanisms. In addition, these models will serve as a
resource for pre-clinical testing of therapeutic strategies targeting the DUX4-fl mRNA and protein as
ameliorative treatments for FSHD.
项目总结
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(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 1.74万 - 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:
$ 1.74万 - 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:
$ 1.74万 - 项目类别:
Mechanisms of DUX4 mediated FSHD pathology
DUX4 介导的 FSHD 病理机制
- 批准号:
10554358 - 财政年份:2013
- 资助金额:
$ 1.74万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 1.74万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 1.74万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 1.74万 - 项目类别:
Standard Grant
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 1.74万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 1.74万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 1.74万 - 项目类别:
Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
- 批准号:
2230829 - 财政年份:2023
- 资助金额:
$ 1.74万 - 项目类别:
Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 1.74万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 1.74万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 1.74万 - 项目类别:
Grant-in-Aid for Scientific Research (C)