Induced Pluripotent Stem Cells for Modeling Congenital Deafness

用于模拟先天性耳聋的诱导多能干细胞

• 批准号: 8510855
• 负责人: Eri Hashino
• 金额: $ 23.4万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510855
• 关键词: Accounting; Acoustic Nerve; Afferent Neurons; Affinity; Autologous; Binding; Biological Models; Birth; CHARGE syndrome; Cell Differentiation process; Cell model; Cells; ChIP-seq; Charge; Chromatin; Clinical; Congenital Abnormality; Congenital Disorders; DNA-Binding Proteins; Data; Defect; Development; Disease; Disease Progression; Ear; Ectopic Expression; Enzymes; Etiology; Exhibits; Fibroblasts; Functional disorder; Gene Targeting; Genes; Genetic Enhancer Element; Genetic Transcription; Genome; Genomics; Goals; Hereditary Disease; Histone H3; Human; Human Genetics; In Vitro; Knowledge; Labyrinth; Lead; Maps; Modeling; Monitor; Mutation; Pathogenesis; Patients; Prenatal Diagnosis; Replacement Therapy; Sampling; Semicircular canal structure; Skin; Somatic Cell; Staging; Stem cells; Syndrome; System; Therapeutic Agents; Therapeutic Intervention; base; cell type; chromatin immunoprecipitation; chromatin remodeling; congenital deafness; experience; hearing impairment; helicase; induced pluripotent stem cell; malformation; nerve stem cell; next generation sequencing; novel therapeutics; public health relevance; stem cell biology; stem cell differentiation; tool; transcription factor

DESCRIPTION (provided by applicant): Charge syndrome is an autosomal dominant genetic disorder typically caused by mutations in the chromodomain helicase DNA-binding protein-7 (CHD7) gene. Inner ear abnormality is the most prevalent clinical feature associated with this disorder, as more than 90% of patients with CHARGE syndrome exhibit malformations of the inner ear structures accompanied by profound hearing loss. However, the mechanism by which mutations in CHD7 leads to the birth defects in CHARGE syndrome is poorly understood. Recent technological advancements in stem cell biology have made it possible to create induced pluripotent stem cells (iPSCs) from a small skin sample of patients with genetic disorders. These patient-derived iPSCs harbor the same genome predisposed to the disorder, and thus serve as a potent human model system to investigate disease-specific pathogenesis and potential therapeutic interventions. The goals of this application are (1) to generate iPSCs with skin fibroblasts isolated from patients with CHARGE syndrome and, using these patient- derived iPSCs, (2) to study disease progression by deriving otic neural progenitors in vitro, and (3) to identify inner ear-specific target genes for CHD7. Our long-term goal is to uncover how mutations in CHD7 cause dysregulated expression of a specific set of genes in the inner ear, resulting in inner ear anomalies and profound hearing loss. The proposed study will provide valuable information on the prenatal diagnosis and targeted treatment of this devastating congenital disorder.

描述（由申请人提供）：电荷综合征是一种常染色体显性遗传疾病，通常由染色体结构域解旋酶dna结合蛋白-7 （CHD7）基因突变引起。内耳异常是与该疾病相关的最普遍的临床特征，因为超过90%的CHARGE综合征患者表现为内耳结构畸形并伴有重度听力损失。然而，CHD7突变导致CHARGE综合征出生缺陷的机制尚不清楚。干细胞生物学的最新技术进步使得从遗传疾病患者的小皮肤样本中制造诱导多能干细胞（iPSCs）成为可能。这些患者衍生的iPSCs含有相同的易患该疾病的基因组，因此可以作为研究疾病特异性发病机制和潜在治疗干预措施的有效人类模型系统。该应用的目的是：(1)用从CHARGE综合征患者分离的皮肤成纤维细胞生成iPSCs，并使用这些患者来源的iPSCs，(2)通过体外提取耳神经祖细胞来研究疾病进展，(3)鉴定CHD7内耳特异性靶基因。我们的长期目标是揭示CHD7突变如何导致内耳中一组特定基因的表达失调，从而导致内耳异常和重度听力损失。提出的研究将提供有价值的信息产前诊断和有针对性的治疗这种毁灭性的先天性疾病。