Many Americans suffer from vestibular dysfunction, which can reduce the quality of life and increase the risk for falls and premature death. A major cause of vestibular dysfunction is the loss of hair cells (HCs), which transduce head movements into neural signals and allow us to maintain gaze, orientation, and control of body movements. Vestibular HCs die as a result of ototoxic drug treatments, inner ear infection, and changes associated with aging. In mammals, vestibular HCs have historically been considered to be irreplaceable, since many symptoms associated with HC loss are permanent. However, several studies have shown that adult rodents can spontaneously replace a small number of HCs after damage, by conversion of non-sensory supporting cells (SCs) into HCs without an intervening cell division. The long-term goal of our research is to develop biologically based methods to replace lost HCs, in order to improve the quality of life of human patients. An 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 vestibular HCs in adult rodents undergo turnover (removal and replacement) in the absence of damage. For example, both differentiating and dying HCs have been detected in the normal (undamaged) vestibular epithelia of adult bats and rodents. If vestibular HCs are continuously replaced in adult mammals, this plasticity would have major implications for HC homeostasis, HC loss during aging, and HC regeneration after damage. The proposed research will directly test the hypothesis that vestibular HCs undergo turnover in normal adult mice.
In Aim 1, we will determine if vestibular HCs are dying and if so, define the position, number, and types that are dying. We will also assess if SCs act as phagocytes to clear HC debris.
In Aim 2, we will use transgenic and knock-in mice to determine if new HCs are added to mouse vestibular epithelia under normal conditions. By tracing the fate of SCs and HCs, we will test the hypotheses that SCs transdifferentiate into type II HCs and type II HCs later convert into type I HCs. We will also determine if SCs are renewed by cell division.
In Aim 3, we will determine if the rates of ongoing HC death and addition are altered with aging.
In Aim 4, we will assess if the rate of SC-to-HC transdifferentiation is altered after near-complete HC destruction. This research project will help to characterize the natural mechanisms for HC replacement present in the vestibular epithelia of young and aged adult mice, which can be exploited to develop better therapies for balance disorders in the near future.
Little is known about the stability of the vestibular hair cell population in adult mammals. The proposed research will test if vestibular hair cells in adult mice undergo turnover (death and replacement) in normal conditions and determine if rates of hair cell addition are altered in old mice or in mice after complete hair cell destruction. The knowledge gained in this project will provide important insights into hair cell homeostasis, aging, and regeneration and will help investigators develop new therapeutic approaches for replacing lost hair cells and restoring balance function to many human patients.