Generation and characterization of a Cre-Lox regulated transgenic zebrafish model of SBMA
Cre-Lox 调节的 SBMA 转基因斑马鱼模型的生成和表征
基本信息
- 批准号:10784254
- 负责人:
- 金额:$ 15.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-11 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AR geneActinsAdultAffectAndrogen ReceptorAndrogensAnimalsBiochemicalBiological AssayBiologyBirthBreedingCAG repeatChemicalsClinical Trials DesignCollaborationsComplementary DNACre lox recombination systemCre-LoxPDNA BindingDNA cassetteDataDedicationsDependenceDiseaseDsRedExhibitsFemaleFunctional disorderFundingFutureGenerationsGeneticGenetic RecombinationGenotypeGlutamineGoalsHeartHistologyHormone ReceptorHumanIn VitroKennedy SyndromeLaboratoriesLengthLibrariesLigand Binding DomainLigandsLimb structureLinkLoxP-flanked alleleMaintenanceMicroscopyModelingModificationMolecularMotorMotor ActivityMotor NeuronsMovementMusMuscle WeaknessMuscular AtrophyNational Institute of Neurological Disorders and StrokeNerve DegenerationNeuroanatomyNeurodegenerative DisordersNeuromuscular DiseasesPartner in relationshipPathogenesisPathologyPatientsPharmaceutical PreparationsPhenotypeProcessProductionPropertyProteinsResearchResearch PersonnelRodent ModelRoleScienceSiteSkeletal MuscleSpecificitySpeedStanoloneStructureStudy modelsSwimmingSystemTerminator CodonTherapeuticTherapeutic InterventionTimeTissuesTransgenesTransgenic OrganismsTranslatingValidationVertebratesZebrafishcell typecohortcostcost comparisonhuman diseasein vivoinducible Cremalemenmodel organismmolecular pathologymotor deficitmotor disordermouse modelmuscle physiologyneuromuscularpatient populationpharmacologicpolyglutaminepromoterreceptorreceptor expressionreceptor functionspinal and bulbar muscular atrophytherapeutic developmenttherapeutic targettransgene expression
项目摘要
Spinal and bulbar muscular atrophy (SBMA or Kennedy's disease) is a slowly progressive, X-linked
neuromuscular disease affecting men. It is caused by the expansion of a CAG repeat within the androgen
receptor (AR) gene, encoding a glutamine tract in the protein. With no cure or therapy, identifying potential
therapeutic interventions for this patient population is pressing. We aim to create a Cre-inducible, low cost, and
high-throughput model of SBMA using zebrafish. Discoveries made from zebrafish research are highly
translatable to humans since zebrafish are vertebrates with extensive structural homology to human
neuroanatomy and muscle physiology. More specifically for SBMA patients, zebrafish express an AR that is
highly homologous in structure and function to human AR. Cre-inducibility of the human AR transgene will enable
the production of founder lines that are able to express high levels of the toxic polyglutamine-expanded AR. We
hypothesize this will lead to robust motor dysfunction in larval zebrafish. These larval zebrafish modeling SBMA
will be amenable to quick (over 1-2 weeks) chemical and drug library screens, or genetic modification(s) to
identify modulators of motor function. Such assays could be set up within only a few days and at a very low cost
compared to such assays in rodent models. Moreover, tissue specific Cre zebrafish lines can be crossed with
these SBMA zebrafish in future studies to investigate the relative role of motor neurons verses skeletal muscle
in the onset and progression of SBMA pathogenesis. A better understanding of the relative roles of each of these
cell types in disease will support clinical trial design for SBMA patients. Further, because SBMA shares properties
with other neurodegenerative, neuromuscular, and polyglutamine diseases, therapeutic targets identified in the
SBMA zebrafish model may also be applicable to some of these other disorders.
脊髓延髓肌萎缩症(SBMA或肯尼迪病)是一种缓慢进行性,X连锁
影响男性的神经肌肉疾病它是由雄激素内CAG重复序列的扩增引起的。
受体(AR)基因,编码蛋白质中的谷氨酰胺段。在没有治愈或治疗的情况下,
对这一患者群体的治疗干预是紧迫的。我们的目标是创造一个铬诱导,低成本,
使用斑马鱼的SBMA的高通量模型。从斑马鱼研究中获得的发现是高度
因为斑马鱼是与人类具有广泛结构同源性的脊椎动物,
神经解剖学和肌肉生理学。更具体地说,对于SBMA患者,斑马鱼表达AR,
在结构和功能上与人AR高度同源。人AR转基因的Cre诱导将使
产生能够表达高水平的毒性聚谷氨酰胺扩增的AR的创始细胞系。我们
假设这将导致斑马鱼幼鱼强健运动功能障碍。这些模拟SBMA的斑马鱼幼体
将适合快速(超过1 - 2周)化学和药物库筛选,或遗传修饰,
识别运动功能调节剂。这样的分析可以在短短几天内建立起来,而且成本非常低
与啮齿动物模型中的此类测定相比。此外,组织特异性Cre斑马鱼系可以与
这些SBMA斑马鱼在未来的研究,以调查运动神经元与骨骼肌的相对作用,
在SBMA发病机制的发生和发展中的作用。更好地理解每一个的相对作用,
疾病中的细胞类型将支持SBMA患者的临床试验设计。此外,由于SBMA共享房产
与其他神经退行性疾病、神经肌肉疾病和多聚谷氨酰胺疾病,
SBMA斑马鱼模型也可能适用于这些其他疾病中的一些。
项目成果
期刊论文数量(0)
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{{ truncateString('Heather L Montie', 18)}}的其他基金
Generation and characterization of a zebrafish model of SBMA
SBMA 斑马鱼模型的生成和表征
- 批准号:
9435195 - 财政年份:2017
- 资助金额:
$ 15.16万 - 项目类别:
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