Tools for the study of hair cell regeneration in the inner ear.
Half of all adults will suffer from some degree of hearing loss, by the time they reach retirement age. Both genetic and environmental factors (loud noise, aminoglycoside antibiotics, chemo-therapeutic drugs such as cisplatin) contribute to hearing loss. This age-dependent hearing loss (presbycusis) is most commonly caused by the death of sensory hair cells in the inner ear. Regeneration of lost cochlear sensory hair cells does not occur in mammals, including humans, with the result that age-dependent hearing loss is permanent. However, aside from prosthetics such as hearing aids and the cochlear implant, developing the tools to induce regeneration in the sensory epithelia of the inner ear of humans offers the only hope for the millions of people who suffer from deafness due to hair cell loss.
In contrast, other vertebrates, such as birds, can regenerate their hair cells by the stimulated cell division and then differentiation of neighboring cells known as supporting cells. Our previous studies in mice indicate that some supporting cells in the mouse inner ear retain a latent ability to divide and turn into hair cells (White et al., 2006), although under normal circumstances they never do. Thus, these cells represent a target population of cells that may be "manipulated" to regenerate hair cells, or alternatively, that might be a source of adult stem cells that could be transplanted into the damaged inner ear for therapeutic purposes. However, there are several different types of supporting cells that can be recognized morphologically and which serve different functions in the inner ear. Currently, the number of molecular markers for these different sub-populations of supporting cells is very limited, and there are no good ways to physically separate and purify them so that their individual regenerative capacity can be tested. Nor are there ways of growing and expanding the small population of supporting cells for experimentation or therapeutic purposes.
In the first and second aims of this proposal, we will develop tools for the molecular identification of these sub-populations of supporting cells, as well as new ways to purify them from the general supporting cell population. In addition, we propose to develop new ways to grow them in culture, so that we can increase the number of available cells for experimental characterization. In parallel, we propose to adapt these newly developed techniques to purify and grow supporting cells from rare human inner ear tissue that is available as a result of special inner ear surgery. In a final aim, we propose to develop genetic tools to permanently mark supporting cells, so that we can follow the fate of these cells and their progeny after their manipulation both in the animal and in our culture dishes. This tool will be crucial for testing the efficacy of any pre-clinical trial involving manipulation or transplantation of progenitors/supporting cells.
Hearing loss affects millions of Californians. Both genetic and environmental factors (such as loud noise, aging, and commonly used drugs such as aminoglycoside antibiotics and chemo-therapeutic drugs such as cisplatin) contribute to hearing loss. All forms of hearing loss, either age-related, as among the baby boomers; noise-induced, as is common in the military and many manufacturing and construction professions; or drug-induced, as is common following chemotherapy for cancer, are most commonly caused by the death of sensory hair cells in the inner ear. Regeneration of lost sensory hair cells does not occur in mammals, including humans, with the result that hearing loss is almost always permanent. Aside from prosthetics such as hearing aids and the cochlear implant, developing the tools to induce regeneration in the sensory epithelia of the inner ear of humans offers the only hope for the millions of people who suffer from deafness due to hair cell loss.
According to the National Institutes of Deafness, approximately 1 in 2000 children born in the US, including California, are born with congenital hearing loss, making it the most common birth defect. Babies and children learn language and communication through listening to their parents or caregivers, a process that is disrupted if hearing loss is not detected and corrected.
According to the Department of Veterans Affairs, of the 1.3 million service men who have served in Iraq or Afganisitan, 58,000 are currently on disability due to hearing loss and an additional 78,000 due to tinnitus (ringing in the ear), making noise induced hearing loss the #1 disability of returning veterans.
Finally, age-related hearing loss -- presbycusis -- is the leading cause of deafness in the population as a whole, with over 50% of adults suffering significant hearing loss by the age of 65 (Davis et al., 2003; Seidman et al., 2002). California's population of people older than 65 will begin a rapid expansion in 2010, and by 2025 will have doubled from the current ~3.5 million older adults, to around 7 million by the year 2025. Half of this elderly popualtion, 3.5 million people, are predicted to experience significant hearing loss, making hearing loss a growing epidemic in the state.
Our long-term research goal is the treatment of deafness and balance disorders through the stimulated regeneration of sensory hair cells in the inner ear. The work described here will greatly aid this endeavor by providing tools for the study of hair cell progenitors/stem cells from the inner ear. Based on a comparison to other animals that are able to regenerate their hearing, and our own recently published findings, supporting cells represent the most likely target for future therapeutic manipulations,including the derivation of adult stem cells, to bring about hair cell regeneration in humans.