Genomic Characterization of cochlear maturation and injury response in mice

Washington University, Saint Louis MO

Investigators

Linked publications & trials

Abstract

FGF20-regeneration Genomic characterization of cochlear maturation and injury response in mice Summary Damage to sensory hair cells (HC) accounts for a large proportion of the age-related hearing loss affecting people over the age of 65 and there are no biologically based therapies to restore hearing in sensorineural damaged inner ears. There is thus a great need for therapeutic methods to restore damaged sensory cells in the inner ear and to prevent further damage to sensory cells and their associated supporting cells. Although the adult mammalian cochlea cannot regenerate following loss or damage of HCs, neonatal mice supporting cells (SC) have a limited ability to reenter the cell cycle and transdifferentiate into HCs following HC loss or damage, and birds and amphibians can fully regenerate lost or damaged HCs and fully recover hearing. The genetic programs responsible for the differential regenerative capacity of the neonatal mammalian cochlea (and the avian and amphibian inner ear) compared to the adult mammalian inner ear are not known. We hypothesize that: 1) specific genetic pathways are activated in the SCs or nearby epithelial cells in the neonatal mammalian cochlea following HC loss or damage that facilitate regeneration, and that 2) these pathways are either silenced or inhibited by interfering pathways in the adult mammal to prevent regeneration. Our goal is to identify such genetic pathways using unique genetic tools that we have recently used successfully to study gene expression in the developing cochlea. Existing strategies that are being used to interrogate gene expression in the inner ear of neonatal and adult mice rely on genetic lineage labeling, dissection of the cochlear duct, cellular dissociation, and fluorescent activated cell sorting. Potential problems with this approach include inherent changes in gene expression following cell dissociation and sorting that could mask physiologically important functional changes, and the lack of genetic tools that can target all of the relevant cell populations that have the potential to respond to HC loss or damage (SCs, HCs, and cells of the greater epithelial ridge, GER). To address these problems, we will employ unique genetic tools to target this cell population, to quickly and specifically ablate HCs, rapidly capture expressed and translating genes using the technique of Translating Ribosome Affinity Purification (TRAP), and sequence all captured mRNAs in the neonatal and mature inner ear. The combination of genetic technologies and next generation RNA sequencing will provide an unbiased discovery of genetic changes that occur during cochlear maturation and during the response of the cochlea to HC ablation. This thorough understanding of differentially regulated signaling pathways during inner ear maturation and regeneration will help explain the loss of the ability of the mature inner ear to regenerate after injury and will provide new targets to facilitate the design of treatments for sensorineural hearing loss.