- Prevention of hearing loss
- Hair cell regeneration
- Improving the cochlear implant
- Recovery from blast-induced hearing loss
- Mechanisms of immune resistance in otitis media
- Mechanisms of recovery from middle ear infection
- Drug delivery to the middle and inner ear
I am involved in a variety of aspects of otologic research. This includes a major focus on auditory neuroscience as it applies to preventing hearing loss and restoring hearing. A second major interest is otitis media, and how the natural protective and recovery responses of the middle ear can be enhanced to prevent ear infections or speed their resolution. Finally, I am working to develop new means to deliver drugs to the middle and inner ears.
As Director of Research for Otolaryngology/Head and Neck Surgery I support the research efforts of other members of the Division. In addition, I am Principal Investigator of the Division’s NIH training grant that provides one year of dedicated research time for each of our residents.
Sensorineural Hearing Loss
A major area of research is the biology of the sensory cells of the inner ear, focused upon cellular mechanisms that lead to hair cell loss. Funded by the Veterans Administration (VA), we identifying the cellular pathways that underlie sensory cell death, leading to new means of preventing hair cell and hearing loss. In this project we also investigate the regeneration of hair cells that have previously been lost. We are characterizing the regulation of genes that control the generation of hair cells by transcription factor networks and epigenetics.
Another focus of my laboratory is the control of cochlear ganglion neuron survival and neurite growth. In a project funded by the VA, we study how neurites can be induced to grow toward a cochlear implant in a patterned manner, to increase the sensitivity and channel number of these hearing restoration devices.
A third project investigates the recovery of hearing following blast injury to the cochlea. Funded by the Department of Defense and industry, we study the time course of hearing recovery after blast exposure. This provides information on the potential for hearing improvement after different levels of blast.
In a project funded by the National Institutes of Health (NIH), I study how the response of middle ear cells and tissues contributes to the defense of the ear from infections. The purpose of this work is to discover means of enhancing the natural protective responses of the middle ear, as alternatives to antibiotics and decongestants.
A second project funded by the NIH is focused up0on mechanisms by which the middle ear recovers from infection, This includes identifying natural pro-recovery compounds and cells that are produced in the middle ear as infections resolve, and reduce the inflammatory response to bacteria. These compounds and cell components are potential agents that could be used to speed recovery of chronic otitis media.
In a project funded by the NIH and Action on Hearing Loss, we have identified a new mechanism for delivering drugs to the middle ear. Using the technique of phage display, we identified a compound that can delivery drugs across the intact tympanic membrane.
I am also a scientific co-founder of Otonomy, Inc., a biotechnology company that specializes in mechanisms of drug delivery to the ear. The company, funded by venture capital, is developing drug formulations that can be injected through the tympanic membrane to support long-term supply of pharmacotherapy to the middle ear for the treatment of hearing and balance disorders as well as ear infections.
Selected Recent Publications
- Lai Y, Di Nardo A, Nakatsuji T, Leichtle A, Yang Y, Cogen AL, Wu ZR, Hooper LV, Schmidt RR, von Aulock S, Radek KA, Huang CM,
Ryan AF, Gallo RL. Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury.
Nature Med 15(12):1377-1382, 2009. PMID: 19966777
- Leichtle A, Hernandez M, Ebmeyer J, Yamasaki K, Lai Y, Radek K, Choung YH, Euteneuer S, Pak K, Gallo R, Wasserman SI,
Ryan AF. CC chemokine lagand 3 overcomes the bacteriocidal and phagocytic defect of macrophages and hastens recovery from experimental otitis media in TNF-/- mice.
J Immunol 184: 3087-3097, 2010. PMID: 20164426
- Masuda M, Dulon D, Pak K, Mullen L, Li Y, Erkman L and
Ryan AF. Regulation of the pou4f3 gene by 5’DNA.
Neurosci 197:48-64, 2011. PMID: 21958861
- Leichtle A, Hernandez M, Lee J, Pak K, Webster N, Wasserman SI,
Ryan AF. The role of DNA sensing and the innate immune receptor TLR9 in otitis media.
Innate Immun 18: 3-13, 2012. PMID: 21239460
- Masuda M, Pak K, Chavez E,
Ryan AF. TFE2 and GATA3 enhance induction of POU4F3 and myosin VIIa positive cells in nonsensory cochlear epithelium by ATOH1. Dev Biol 372(1):68-80, 2012. PMID: 22985730
- Euteneuer S, Yang KH, Chavez E, Leichtle A, Loers G, Olshansky A, Pak K, Schachner M,
Ryan AF. Glial cell line-derived neurotrophic factor (GDNF) induces neuritogenesis in the cochlear spiral ganglion via neural cell adhesion molecule (NCAM).
Mol Cell Neurosci 54C:30-43, 2012. PMID: 23262364.
- Yan D, Zhu Y, Walsh T, Xie D, Yuan H, Sirmaci A, Fujikawa T, Wong AC, Loh TL, Du L, Grati M, Vlajkovic SM, Blanton S,
Ryan AF, Chen ZY, Thorne PR, Kachar B, Tekin M, Zhao HB, Housley GD, King MC, Liu XZ. Mutation of the ATP-gated P2X(2) receptor leads to progressive hearing loss and increased susceptibility to noise.
Proc Natl Acad Sci U S A 110(6):2228-2233, 2013. PMID: 23345450
- Kurabi A, Pak K, Dang X, Coimbra R, Eliceiri BP,
Ryan AF, Baird A. ECRG4 attenuates the inflammatory proliferative response of mucosal epithelial cells to infection.
PloS One 8:e61394, 2013. PMID: 23626679.
- Housley GD, Morton-Jones R, Vlajkovic SM, Telang RS, Paramananthasivam V, Tadros SF, Wong AC, Froud KE, Cederholm JM, Sivakumaran Y, Snguanwangchai P, Khakh BS, Cockayne DA, Thorne PR,
Ryan AF. ATP-gated ion channels mediate adaptation to elevated sound levels.
Proc Natl Acad Sci USA 110: 7494-7499, 2013. PMID: 23592720.
- Brand Y, Sung M, Chavez E, Wei E, Pak K, Housley GD, Bodmer D,
Ryan AF. Neural cell adhesion molecule L1 modulates type I but not type II inner ear spiral ganglion neurite outgrowth in an in vitro alternate choice assay. J Molec Neurosci June 13, 2013 [Epub ahead of print]. PMID: 23760987.
|Stephen I. Wasserman, MD||UCSD Department of Medicine|
Division of Allergy & Immunology
|Andrew Baird, PhD||UCSD Department of Surgery|
Division of Trauma
|Nicholas Webster, PhD||UCSD Department of Medicine|
Division of Endocrinology & Metabolism
|Gary D. Housley, PhD||University of New South Wales|
Department of Neuroscience
|Jeffrey Sakamoto||Michigan State University|
Department of Biomedical Engineering