Replacement of vestibular hair cells in normal and damaged adult mice

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DESCRIPTION (provided by applicant): Vestibular epithelia contain sensory hair cells (HCs) that transduce spatial movements to neural signals necessary for balance and coordination. HC death associated with damage or aging causes balance disorders in millions of people worldwide. Adult mammals, including humans, demonstrate a small capacity to replace lost HCs. Most studies suggest that supporting cells (SCs) directly convert into HCs after HC loss, and very few, if any, HCs are born directly from SC division. However, only limited HC regeneration occurs naturally in mammals after HC loss, and it is not sufficient to restore vestibular function. The long-term goal of this research is to develop biologically based methods to regenerate all lost HCs and to improve the quality of life of human patients. Complete understanding of HC and SC population dynamics in adult mammals under normal conditions is needed to achieve this goal. It is generally assumed that HCs are not added to the vestibular epithelia of mature mammals unless damage occurs. However, indirect evidence from several laboratories suggests that vestibular HCs in adult rodents may undergo normal turnover in the absence of damage. For example, immature HCs and HCs undergoing apoptosis or phagocytosis, have been detected in normal adult rodent vestibular organs. This proposed research will utilize several transgenic mouse lines to label and track HC and SC populations in the vestibular epithelia of normal (undamaged) adult mice over time. These methods will be used to test the hypotheses that new HCs are continually added to the vestibular epithelia of adult mice, and SCs directly convert into HCs, in the absence of HC damage. Further, this approach will be applied to test the hypothesis that HC loss does not increase the normal rate of HC addition. This research will help characterize natural mechanisms for hair cell replacement that are present within adult and aged mammalian vestibular epithelia and can be exploited to develop better therapies for balance disorders in the near future.