权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Human iPSC and glial chimeric modeling of Pelizaeus-Merzbacher Disease

Pelizaeus-Merzbacher 病的人类 iPSC 和神经胶质嵌合模型

基本信息

批准号：
9113685
负责人：
Paul Joseph Tesar
金额：
$ 37.12万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113685
关键词：
Address Adult Automobile Driving Brain CRISPR/Cas technology Cell Line Cell Therapy Cells Cessation of life Child Childhood Chimera organism Deterioration Disease Endoplasmic Reticulum Engineering Engraftment Etiology Exhibits Foundations Functional disorder Generations Genes Genetic Genotype Goals Health Hereditary Disease Heterogeneity Human Image In Vitro Individual Laboratories Link Longevity Mediating Methods Modeling Molecular Molecular Genetics Motor Multiple Sclerosis Mus Mutation Myelin Myelin Proteins Neuraxis Neurodegenerative Disorders Neurologic Neurologic Dysfunctions Neurons Oligodendroglia Pathogenesis Pathology Patients Pelizaeus-Merzbacher Disease Pharmaceutical Preparations Pharmacotherapy Phenotype Proteins Proteolipids Protocols documentation Rare Diseases Shivering Stem cells System Technology Testing Therapeutic Transplantation United States base clinical phenotype clinically relevant disease phenotype drug discovery endoplasmic reticulum stress gene correction gene therapy genotyped patients humanized mouse improved in vivo induced pluripotent stem cell innovation insight leukodystrophy molecular phenotype mouse model myelination nuclease stem cell technology targeted treatment transcriptome treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Pelizaeus-Merzbacher disease (PMD) is a severe X-linked pediatric neurodegenerative disorder impacting myelination in the central nervous system. PMD results from mutations in the PLP1 gene which encodes the most prevalent myelin protein of the central nervous system. PMD exhibits a spectrum of clinical phenotypes that reflect wide genotypic heterogeneity, but nearly all forms of the disease result in progressive neurological deterioration and death, often during childhood. With the advent of induced pluripotent stem cell (iPSC) technologies and cell fate reengineering, we have now developed robust methods for generation of patient- specific oligodendrocytes in vitro. This provides new access to model the phenotypic and genotypic spectra within PMD. We have generated a large comprehensive panel of characterized iPSC lines from PMD patients that spans the full genotypic and phenotypic spectrum of the disorder. In this application we will focus on the patient-specific molecular and cellular deficits in PMD patient oligodendrocytes and provide platforms for testing of therapeutics. Aim 1 will use the robust human iPSC-derived oligodendrocyte differentiation protocols that we have developed as a phenotyping platform for examining PMD patient oligodendrocyte dysfunction and assessing the ability of clinically-relevant pharmacologic therapies to rescue individual phenotypes in vitro. Aim 2 will use an approach by which we can produce humanized chimeric mice whose oligodendrocytes and myelin have been largely replaced by human iPSC-derived oligodendroglia. Combining this technology with PMD iPSC lines from our panel will enable us to generate patient-specific PMD glial chimeras and examine oligodendrocyte dysfunction in vivo. In Aim 3 we will test if genetically-corrected PMD iPSC-derived OPCs show restored myelination capacity in glial chimeric mice. Together, these studies should provide us new insight into the cell and molecular deficits driving the pathogenesis of PMD. Our goal is to establish in vitro and in vivo platforms for the modeling and treatment of PMD, while providing a broad strategy for the treatment of hereditary disorders of myelin.