The senses of hearing and balance depend upon hair cells, the sensory receptors of the inner ear. Hair cells transduce mechanical stimuli into electrical activity. Loss of hair cells or damage to the transduction apparatus, the stereocilium bundle on the surface of the hair cell, as a result of aging or exposure to noise and ototoxic drugs is the major cause of noncongenital hearing and balance deficits. Studies in the last two decades have demonstrated that lost hair cells can be replaced by production of new hair cells in birds and lower vertebrates. Hair cell regeneration is limited in mammals, but there is evidence to suggest that damaged hair cells may survive and undergo intracellular repair. In this proposal, we will determine whether mammalian cochlear hair cells could survive after loss of stereocilia. If the hair cells can survive for some time, this window of opportunity can be crucial for genetic or chemical therapeutic interventions in order to repair hair bundles. Thus, we will explore the feasibility of regenerating stereocilia using a gene therapy approach. We have two specific aims for this Exploratory/Developmental research.
In Aim 1, we will examine the fate of mammalian hair cells after their stereocilia have been intentionally removed to determine whether hair cells can survive and develop.
In Aim 2, we will determine whether over-expression of myosin-15a and whirlin, two genes that are involved in stereocilium morphogenesis, can promote hair-bundle repair/regeneration and whether the newly regenerated stereocilia are functional. The experiments will be carried out in the cultured organ of Corti from neonatal gerbils. The hair bundles of outer hair cells in a designated area of the organ of Corti will be removed by a small suction pipette. Hair-cell survival/development and stereocilium morphology/function will be examined using immunohistochemistry (with confocal microscopy), time-lapse imaging, scanning electron microscopy, and electrophysiology. This project is highly significant, since exploring the strategies of maintaining, rescuing, and repairing injured hair cells are essential to the biological remediation and prevention of hair cell-related hearing loss and deafness.
Because the majority of Americans with hearing loss, some 30 million in all, have some kind of hair cell damage, understanding the cellular process of damage repair and exploring the possibilities of rescuing and repairing injured hair cells are essential to the biological remediation and prevention of hair cell-related hearing loss and deafness.
|Yang, Shi-Ming; Chen, Wei; Guo, Wei-Wei et al. (2012) Regeneration of stereocilia of hair cells by forced Atoh1 expression in the adult mammalian cochlea. PLoS One 7:e46355|
|Jia, Shuping; Yang, Shiming; Guo, Weiwei et al. (2009) Fate of mammalian cochlear hair cells and stereocilia after loss of the stereocilia. J Neurosci 29:15277-85|