听力损失的谱系重编程：药物筛选和基因治疗方法的发展-猫眼课题宝

听力损失的谱系重编程：药物筛选和基因治疗方法的发展

批准号：

9292295

负责人：

Justin Kawika Ichida

金额：

$58.05万

依托单位：

UNIVERSITY OF SOUTHERN CALIFORNIA

依托单位国家：

美国

项目类别：

财政年份：

2016

资助国家：

美国

项目状态：

已结题

起止时间：

2016-07-01 至 2021-06-30

来源：

https://reporter.nih.gov/project-details/9292295

关键词：

ATAC-seq Address Adult Alpha Cell Animals Benchmarking Cell Differentiation process Cells Cessation of life Chromatin Chromatin Structure Development Disease Disease model Ear Embryo Engineering Epigenetic Process Epithelium Failure Fibroblasts Functional disorder Gene Expression Genes Genetic Genetic Models Gentamicins Growth Hair Cells Hearing problem Hereditary Disease Human In Vitro Labyrinth Lead Mammals Mediating Modernization Molecular Analysis Morbidity - disease rate Mus Mutation Natural regeneration Neurodegenerative Disorders Neurons Organ of Corti Pathogenesis Pathway interactions Pharmaceutical Preparations Population Potassium Channel Pre-Clinical Model Preclinical Drug Evaluation Property Prosthesis Protocols documentation Regenerative response Replacement Therapy Residual state Sensorineural Hearing Loss Sensory Sensory Hair Somatic Cell Son Supporting Cell Target Populations Techniques Technology Testing Transgenic Mice Variant base cell type deafness disability drug development drug discovery embryonic stem cell equilibration disorder experimental study gene therapy hair cell regeneration hearing impairment high throughput screening human disease improved in vivo insight model development mutant ototoxicity ototoxin pre-clinical preclinical development tool transcription factor transcriptome sequencing

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Project Summary/Abstract: Deafness and balance disorders resulting from the loss of sensory hair cells of the inner ear are a major cause of disability and morbidity in the US. In mammals, the cells of the various sensory epithelia of the inner ear arise embryonically and subsequently do not regenerate if damaged (Rubel et al., 2013). Hearing loss resulting from the death of hair cells in the organ of Corti is thus permanent, and treatments aimed at reversing hearing loss through stimulated regeneration of hair cells are badly needed. However, experimentation on the cells of the inner ear is difficult due to their small number and extreme inaccessibility in the adult. As a result, modern techniques of cell and molecular analysis and drug discovery have been difficult to apply, and aside from prosthetics, treatment options for sensorineural deafness remain few. To overcome these problems, and in pursuit of new treatments for hair cell loss, we have used powerful new “direct lineage reprogramming” technologies, originally developed for neuron-specific reprogramming (Son et al., 2011; Vierbuchen et al., 2010), to generate hair cell-like cells in vitro, directly from mouse and human somatic cells (fibroblasts and inner ear supporting cells). This advance allows a new range of experimentation into the mechanisms of hair cell differentiation, the development of preclinical models of genetic hearing loss (disease modeling), high-throughput screening for drug discovery related to regeneration and ototoxicity, and the application of gene therapy approaches to the problem of hair cell regeneration. The Aims of the proposal include: 1) Development of improved reprogramming strategies to induce mouse and human hair cell-like cells. 2) Development of a drug screen for ototoxicity, and an in vitro disease model of genetic hearing loss. 3) A test of reprogramming in a preclinical model of hair cell regeneration/replacement in long-deafened mice.

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