Study of SBMA mutant AR transcriptional network in stem cell-derived motor neurons and skeletal muscle
干细胞源性运动神经元和骨骼肌中SBMA突变体AR转录网络的研究
基本信息
- 批准号:10599883
- 负责人:
- 金额:$ 17.48万
- 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:2020-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AR geneAddressAdultAffectAndrogen ReceptorAndrogensAnimal ModelAtrophicAwardBiological AssayCRISPR interferenceCell DeathCellsCentral Nervous SystemChIP-seqConsensusDataData SetDiseaseDisease modelEtiologyFamilyFertilityGene ExpressionGenesGeneticGenetic TranscriptionGenomicsGlutamineGoalsGrantGynecomastiaHi-CHumanHuntington DiseaseIn VitroInheritedInternationalJournalsKennedy SyndromeLettersLigandsLinkLiteratureLuciferasesManuscriptsMentorsMentorshipMitochondriaMolecularMotor Neuron DiseaseMotor NeuronsMuscleMuscle WeaknessMutationNeurodegenerative DisordersNeuromuscular DiseasesNeuronal DysfunctionNeurosciencesPathogenesisPathologyPathway interactionsPatientsPhenotypeQuantitative Reverse Transcriptase PCRReporter GenesResearchScientistSkeletal MuscleSpecific qualifier valueStanoloneTestingTherapeuticTimeTissuesToxic effectTrainingTranscriptional RegulationUniversitiesValidationWorkcell typechromatin immunoprecipitationcomparison controldeep sequencingdefined contributiondifferential expressionexperiencefunctional genomicsgene repressiongenome-widehuman stem cellsinduced pluripotent stem cellmembermotor controlmotor neuron degenerationmutantnervous system disorderoverexpressionpolyglutamineprofessorprogramsresponsible research conductskeletal muscle wastingspinal and bulbar muscular atrophystem cell biologystem cell modelstem cellssymposiumtheoriestherapy developmenttooltranscription factortranscriptome sequencingtranscriptomics
项目摘要
SUMMARY
X-linked spinal and bulbar muscular atrophy (also known as SBMA or Kennedy's disease) is a rare
neuromuscular disorder characterized by adult-onset proximal muscle weakness due to lower motor neuron
degeneration. SBMA patients display signs of androgen insensitivity, including gynecomastia, reduced fertility,
and testicular atrophy. SBMA, is caused by a CAG-polyglutamine (polyQ) repeat expansion in the androgen
receptor (AR) gene and is one member of a family of nine CAG-polyQ repeat disorders that includes
Huntington’s disease. For decades, research into the basis of neurological disease focused upon the
contribution of neuronal dysfunction to disease pathogenesis. However, over the last ten years, there has been
growing evidence in the motor neuron disease field that challenges the prevailing neurocentric theory of the
etiology of many neurological diseases. Recently, we have identified increased cell death in control motor
neurons subjected to conditioned media from SBMA iPSC-derived skeletal muscles compared to control
derived skeletal muscles. This finding emphasizes the importance of muscle toxicity in SBMA disease
pathogenesis. For therapeutic purposes, however, there is lack of consensus in the literature. Different groups
have been able to demonstrate successful treatments targeting either the skeletal muscle or the central
nervous system using different SBMA animal models. Consequently, there is a need for studies of the SBMA
AR-mutation on the affected cell types, skeletal muscle and motor neurons, in a human background.
Therefore, the applicant, Dr. Helen C. Miranda, is proposing to combine her considerable experience in
stem cell biology and motor neuron disease modeling to a mentorship in functional genomics, to test the
hypothesis that the AR transcriptional network is tissue-specific in SBMA. This project will test this hypothesis
by combining AR genome wide occupancy and gene expression data sets generated from SBMA and isogenic
controls iPSC-derived skeletal muscle and motor neurons. This work will advance understanding on the
molecular mechanisms of human mutant AR to SBMA pathogenesis and evaluate the utility of iPSC-derived
skeletal muscles and motor neurons tool to develop SBMA in vitro studies. Dr. Miranda is a new Assistant
Professor in the Department of Genetics and the Department of Neuroscience at Case Western Reserve
University. She will devote 75% of her time to research under this award and will supplement her research with
didactic training in genomic and transcriptomic analyses. This training will be comprised of 1) departmental and
university courses, 2) seminars and journal clubs 3) responsible conduct of research courses and 4) national
and international conferences. Dr. Miranda will be mentored by Dr. Anthony Wynshaw-Boris and Dr. Ann
Harris at Case Western Reserve University. These established scientists are both renowned experts in stem
cell biology and functional genomics. Dr. Miranda has met with each of her mentors to discuss this project and
will continue to meet with them at regular intervals (specified in mentorship letters) during the course of this
award. She is expected to produce manuscripts as corresponding or co-corresponding author and be
competitive for R-level grants during the course of this award. This project will integrate Dr. Miranda’s current
expertise with additional training to develop a well-rounded, independent research program.
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)
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Helen C Miranda其他文献
Helen C Miranda的其他文献
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{{ truncateString('Helen C Miranda', 18)}}的其他基金
Human-iPSC derived neuromuscular junctions as a model for neuromuscular diseases.
人 iPSC 衍生的神经肌肉接头作为神经肌肉疾病的模型。
- 批准号:
10727888 - 财政年份:2023
- 资助金额:
$ 17.48万 - 项目类别:
Study of AR transcriptional network in stem cell model of SBMA
SBMA干细胞模型中AR转录网络的研究
- 批准号:
10373083 - 财政年份:2021
- 资助金额:
$ 17.48万 - 项目类别:
Study of AR transcriptional network in stem cell model of SBMA
SBMA干细胞模型中AR转录网络的研究
- 批准号:
10184227 - 财政年份:2021
- 资助金额:
$ 17.48万 - 项目类别:
Study of AR transcriptional network in stem cell model of SBMA
SBMA干细胞模型中AR转录网络的研究
- 批准号:
10581556 - 财政年份:2021
- 资助金额:
$ 17.48万 - 项目类别:
Study of SBMA mutant AR transcriptional network in stem cell-derived motor neurons and skeletal muscle
干细胞源性运动神经元和骨骼肌中SBMA突变体AR转录网络的研究
- 批准号:
10400920 - 财政年份:2020
- 资助金额:
$ 17.48万 - 项目类别:
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