Combination of Compounds A2CE and C18 for Cochlear Hair Cell Regeneration in Adult Mice
Loading...
Authors
Millan V, Fred
Issue Date
2022
Volume
Issue
Type
Thesis
Language
en_US
Keywords
Hair Cells , Regeneration
Alternative Title
Abstract
Hearing loss is a permanent disability that affects a significant percentage of the population, with many interventions relying on secondary medical devices such as cochlear implants, but regeneration of hearing has been an important avenue to explore to restore normal hearing function. Hair cells are a specialized cell type in the inner ear that are crucial for transducing sound into electrical signals that our neurons can interpret. They are post-mitotic, which means once they die or are damaged, they do not regenerate. Previous studies have utilized genetic manipulations in mice to upregulate pro-hair cell fates in a subpopulation of cells that contain stem-cell like markers, called supporting cells, which should push these cells to transdifferentiate and replace lost hair cells in the inner ear. However, due to the nature of these studies and their use of transgenic mouse lines, they are not very translatable to clinical trials as-is. Here, using a combination of compounds that either upregulate a gene of interest or suppress a gene that inhibits regeneration, we aim to produce the first drug-induced regeneration of hair cells in adult mice. In our cocktail we have two drugs Alsterpaullone, 2-Cyanoethyl (A2CE) and proprietary drug Compound 18 (C18). C18 is an up regulator of the gene POU4F3, which has been shown to be sufficient in producing hair cells from supporting cells in transgenic mice. A2CE is a transcriptional inhibitor of p27kip1, which has been shown to have a non-canonical role in suppressing a cofactor for Atoh1, which is an upstream of POU4F3 and is an important developmental gene in hair cell development. We gave transtympanic injections of our drug cocktails to either FVB or Sox2 CreER; Tdtomato mice and collected their cochlea 4 weeks following injections. We found that following injections of our cocktail into the ear, regeneration of immature hair cells expressing both supporting cell markers and hair cell markers were found. We saw high amounts of variance among samples, which significantly impacts the efficacy of our drug cocktail, and needs to be addressed in future studies. From our Sox2 CreER; Tdtomato samples we confirmed that our population of converted hair cells arise from the Sox2 expressing supporting cells, which is consistent with previous genetic models. Future studies should include pharmacokinetic studies focusing on drug distribution through the round window and the inner ear, which we hypothesize may contribute to the high amount of variance amongst the samples.
Description
2022
Citation
Publisher
Creighton University
License
Copyright is retained by the Author.
A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.