Investigation of the molecular mechanisms of ototoxicity.

摘要

Sensory hair cells are essential for transforming the mechanical vibrations of sound into electric signals that our nervous system can interpret. However, sensory hair cells are sensitive to a variety of stresses, including aminoglycoside antibiotics, chemotherapy agents, and environmental noise. The molecular mechanisms of ototoxicity have been under investigation for several decades, yet little is known about the underlying signaling pathways. In Chapter 2 and 3 of this study, we adapted an established technique of organotypic culture of perinatal mouse cochlea to investigate the ototoxicity. With this culture model, we found that CDK2 activity was involved in aminoglycoside-induced hair cell death and that one consequence of its activity was to mediate the transcriptional activity of c-Jun. The involvement of CDK2 was further supported by evidence from utricular cultures and in vivo experiments. Using knockout mice, we demonstrated that p19ink4d, p21kip1 and p53 were not involved in aminoglycoside ototoxicity. In Chapter 6, we profiled the gene expression changes in hair cells after aminoglycoside treatment and found altered expression for genes involved in the general transcription apparatus, translation machinery, mitochondria, DNA damage and repair, stress and apoptosis, JNK pathway and NF-kappaB pathway. Finally, we found that the sensitivity to ototoxins was changed in mCherry-H2B positive hair cells. Our results create a framework for understanding the molecular mechanisms of ototoxicity and the signaling pathways underlying postmitotic hair cell apoptosis.