In the post below, Dr. Alan Cheng discusses the research currently being done in his laboratory, to both prevent and cure hearing loss. Dr. Cheng is an Assistant Professor of Otolaryngology and a Pediatric Otologist – and as such brings first hand knowledge of the effects of hearing loss on children to his research and can visualize the positive impact that a cure for hearing loss could have on their lives:
Hearing loss is a public health problem affecting individuals of all ages, ranging from newborns to the elderly. As a pediatric otologist, I take care of children suffering from this sensory deficit and am often frustrated with the lack of treatment to reverse this disease process. In hopes of preventing and reverting hearing loss, I have been involved in basic research in inner ear biology for the last 10 years. In the inner ear, hair cells are special sensory cells that transduce mechanical energy of sound to neural impulses. Because loss of hair cells underlies many forms of hearing loss, regenerating hair cells is a promising approach to reversing hearing loss and thus a priority in my research program.
Specifically, my laboratory is interested in understanding how the development and regeneration of hair cells are regulated. Using mouse models that recapitulate the development of human cochlea, we have been characterizing specific stem/progenitor cell types that can give rise to hair cells and define specific cues that are essential in this process. In our work that was recently published in the Proceedings of the National Academy of Sciences, we described a subset of supporting cells in the cochlea with progenitor cell potentials and the innate ability to generate new hair cells, and that a self-renewal signal is able to expand this cell population. Because in other organ systems there exist a hierarchy of stem/progenitor cells, other members in my laboratory are currently characterizing another progenitor cell populations and defining the relationship between them.
A fundamental question in stem cell biology is: how do stem/progenitor cell decide to differentiate into more mature cell type? Also, how are progenitors different between the auditory and vestibular organs in the inner ear, all of which need hair cells to function? Moreover, how do progenitors decide to become inner or outer hair cells, both of which have distinct properties. In our experiments, we ask these questions when probing these stem/progenitor cell types in the inner ear as we seek to control the extent of cochlear hair cell development.
In parallel to investigating hair cell development, my research group is studying how hair cells are regenerated in mammals from several angles. First, while no hair cell regeneration and hearing recovery has been observed in the mammalian cochlea, a limited extent of hair cell regeneration occurs in the gravity sensing inner ear organ the utricle. Using knowledge gained from others and our work, we have noted that molecular events during regeneration resemble those of development. Ongoing work involving damage models both in culture and at the whole animal level examines whether manipulation of these molecular events can enhance hair cell regeneration.
Why do we want to look at hair cell regeneration in the whole animal? Much of previous work on mammalian regeneration has emphasized in vitro (in a petri dish) experiments, which has the advantages of ease of manipulations, but lack the feasibility of long term and functional analyses that a whole animal model system offers. To overcome these obstacles, we have established hair cell loss models in transgenic mice allowing long term recovery after damage as well as serial functional studies on live animals. One of the most exciting aspect of our research is that we can correlate hair cell loss and regeneration to functional loss and recovery!
A separate direction of the laboratory is developing novel drugs that prevent hair cell loss. The antibiotic aminoglycoside is a potent anti-bacterial but comes with a high price: a significant (up to 30%) portion of patients receiving this drug can develop hearing loss from hair cell degeneration. In collaboration with Tony Ricci, our group has been characterizing the entry route of this class of drugs into the inner ear sensory cells. With the knowledge of this trafficking mechanism, we are re-designing a new class of antibiotics with the overall goal of them being non-ototoxic.
Dr. Cheng’s recently published paper, in the Proceedings of the National Academy of the Sciences, is titled: Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea. Dr. Cheng will be presenting this paper at the NIH and St. Jude Children’s Hospital in June.