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.
|Effective start/end date||6/1/13 → 5/31/16|
- National Institutes of Health: $195,000.00
- National Institutes of Health: $234,000.00
Induced Pluripotent Stem Cells
Inborn Genetic Diseases
Congenital, Hereditary, and Neonatal Diseases and Abnormalities