Novel Transcription Factors for Regeneration of Functional Outer Hair Cells after Noise Injury
Abstract
Noise induced hearing loss (NIHL) affects performance in military and is irreversible, resulting in a permanent disability to service members. NIHL is primarily caused by damage to cochlear sensory hair cells (HCs), in particular the outer HCs (OHCs). Unfortunately, humans and other mammals cannot replace damaged HCs; however, chicken, fish, and amphibians can replace nonfunctional HCs by a mechanism involving proliferation and conversion of neighboring supporting cells (SCs). Thanks to the ONR support over the past eight years, we were able to regenerate HCs from SCs in vivo in mouse cochleae at neonatal, juvenile and adult ages. We achieved these by genetic manipulations of key transcription factors such as Atoh1 specifically in cochlear SCs. However, the SC-to-HC conversion is inefficient and the regenerated HCs were immature and non-functional. Our results thus suggested that additional transcription factors are needed to promote efficient HC conversion and maturation. Here we propose to test 51 novel transcription factors we recently identified by comparing the gene expression profiles of the newly converted HCs and endogenous OHCs and SCs. Most of these 51 novel candidate genes are not conserved in HC regeneration in chicken, fish or mammalian utricle. We will first test pools of these transcription factors in neonatal mouse cochlear explant culture and identify those that increase the conversion rate or promote OHC maturation. We will then confirm a selected transcription factors in vivo for HC regeneration by creating and characterizing transgenic mouse models which will also be subject to noise injury. Our strategy resembles the Nobel prize winning strategy used by others for cellular conversion in other regenerative systems. Our proposed studies will identify novel transcription factors that can promote regeneration of functional auditory sensory cells after noise injury. These novel factors will serve as therapeutic targets to restore hearing loss and provide insights for regenerative medicine in hearing research.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 26, 2018
- Source ID
- N000141812507
Entities
People
- Jian Zuo
Organizations
- Creighton University
- Office of Naval Research
- United States Navy