DISTANCE FROM THE TOP:
initial

Saul and Ida Epstein Hearing Research Laboratory

The Saul and Ida Epstein Hearing Research Laboratory was established by generous gifts from the Epsteins in 1976. Since that time continuing gifts from the Epsteins, as well as grant and contract funding from the National Institutes of Health, industry-sponsored contracts, and several foundations have supported a wide range of basic hearing research projects. The laboratory is approximately 1,700 square feet and is located in the UCH building at 533 Parnassus Avenue. It includes dedicated facilities for molecular biology, light microscopy, imaging and image analysis, transmission electron microscopy, electrophysiology, psychophysics, recovery surgery, biomedical engineering, and molecular biology. Historically, the Epstein Lab has been world-renowned for its contributions to the development of contemporary cochlear implants - particularly for basic research on central nervous system encoding of electrical stimuli, plasticity following early deafness and applied cochlear implant (CI) stimulation. Our specific focus has been on understanding the structural and functional changes in the cochlea and central auditory system after early deafness, the effects of chronic CI stimulation, and the factors influencing auditory nerve survival. Current research is exploring exciting new virally-mediated gene therapy approaches. Specific areas of interest include 1) evaluating the potential for optimizing CI outcomes using virally-mediated neurotrophin gene therapy to improve auditory nerve survival and 2) exploring the potential for prevention of hearing loss or restoration of hearing in mouse models of human genetic hearing loss.

Patricia A Leake, PhD

Dr. Leake is the Georgia G. Sullivan Professor, Emerita and Director of the Saul and Ida Epstein Laboratory in the UCSF Department of Otolaryngology-Head and Neck Surgery. She is also a member of the faculty of the UCSF/UCB Joint Graduate Program in Bioengineering. Dr. Leake received her PhD in Anatomy from the University of California San Francisco. After completing a postdoctoral fellowship with Dr. Michael Merzenich, Dr. Leake joined the faculty of the Department of Otolaryngology. Her current research focus is on evaluating the feasibility viral mediated neurotrophin gene therapy to promote improved auditory nerve survival in the cochlea after early deafness.

Research Team

  • Omar Akil, PhD, Assistant Professor
  • Chantale Dore, Animal Health Technician
  • Stephen J. Rebscher, MA, Specialist
  • Chirstian Falhman, PhD., Staff Research Associate

Collaborators

  • Omar Akil, PhD
  • Ralph E. Beitel, PhD
  • Cherian Kandathil, MD
  • Larry Lustig, MD
  • Olga Skakhovskaya, MD, PhD

Recent Significant Publications

  1. Leake PA, Hetherington AM, Stakhovskaya O, Rebscher SJ, Bonham B. Effects of brain-derived neurotrophic factor (BDNF) and electrical stimulation on survival and function of cochlear spiral ganglion neurons in neonatally deafened cats. JARO 2013 14(2):187-211
  2. Leake PA, Stakhovskaya O, Rebscher SJ. Effects of Early-Onset Deafness in the Developing Auditory System. Deafness. A. Kral, A.N. Popper and R.R. Fay (eds.), Springer Handbook of Auditory Research. Springer-Verlag, New York, NY. 2013:41-81.
  3. Schoenecker MC, Bonham BH, Stakhovskaya O, Snyder RL, Leake PA. Monopolar intracochlear pulse trains selectively activate the inferior colliculus. JARO 2012 13:655-672.
  4. Leake PA, Hradek GT, Hetherington AM, Stakhovskaya O. Brain-derived neurotrophic factor (BDNF) promotes cochlear spiral ganglion cell survival and function in deafened, developing cats. J. Comp. Neurol. 2011 519:1526-1545
  5. Leake PA, Stakhovskaya O, Hradek GT, Hetherington AM: Factors influencing neurotrophic effects of electrical stimulation in the deafened, developing auditory system. Hearing Res. 2008 242(1-2):86-99.

Omar Akil, PhD

Dr. Akil is an Assistant Professor in the Saul and Ida Epstein Laboratory in the Department of Otolaryngology – Head and Neck Surgery at the University of California, San Francisco. Dr. Akil received his doctoral degree in Biochemistry and Enzymology from the University of Casablanca Morocco. After working as a government administrator in Morocco for two years, he moved to Johns Hopkins where he started his research training, working on the mammalian cochlea and exploring the basis of efferent neuronal transmission and outer hair cell function in the inner ear. Dr. Akil moved to University of California San Francisco in 2004, where he began investigating hearing loss in mouse models of human genetic and acquired forms of deafness. His recent work has focused specifically on the restoration of hearing in mice models of human genetic hearing loss using virally mediated gene therapy.

Research Interests

Molecular biology of hearing, auditory hair cell physiology, genetic deafness, gene therapy and hair cell protection

The primary focus of our lab is the study of the molecular mechanisms of efferent control of the auditory system. There are currently a number of ongoing projects related to this topic, including the role of saposins and synucleins in the auditory system.

Our current work focuses on

  1. Investigating hearing loss in mouse models of human genetic and acquired forms of deafness. We use multidisciplinary approaches, including molecular biology, mouse genetics, mouse behavior, eletrophysiological recording, immunolabeling, histology and others methods in order to understand the important role(s) of specific proteins in the normal function of the cochlea. Our research should help understand how malfunctions of these proteins contribute to sensorineural hearing loss. Increasing knowledge of the underlying molecular and genetic mechanisms that lead to hearing loss raises the possibility for novel therapeutics, such as those based on gene transfer and related methods that influence gene expression in affected tissues.
  2. Utilizing virally-mediated gene therapy to restore hearing in mouse models of specific forms of human genetic hearing loss. This work stems from an initial study in which our lab demonstrated that the inner hair cell glutamate-transporter VGLUT3 is integral to the development of hearing, while a mutation of the transporter causes early profound hearing loss. In follow-up studies, we demonstrated that virally mediated gene therapy can successfully restore the hearing phenotype in a mouse model of this form of genetic deafness. Based on this work, we are currently exploring models of other forms of genetic deafness to determine whether our initial results can be duplicated. It is reasonable to predict that such successful treatment approaches in mouse models of hearing loss will establish a framework for developing gene replacement therapies in humans.

Collaborators

  • Patricia Leake, PhD in “AAV-Mediated Neurotrophin Expression in the Deafened Cochlea” project.
  • Larry Lustig, MD. in most of the projects in progress.
  • Dylan Chan, MD. PhD in “AAV-Mediated Genetic Rescue of Cx26-Associated Hearing Loss” project.

In addition, our interdisciplinary research includes collaboration with

  1. Dr. Tamara Alliston, an orthopedic surgery researcher at UCSF, who is interested in studying cochlear otic capsule development and the role of material properties of bone in hearing. Using animal models and molecular techniques applied to bone growth and development, we are collaborating with Dr. Alliston to examine how the material properties of bone enclosing the inner ear may contribute to hearing or hearing loss. This work may help further understanding of how metabolic abnormalities cause certain types of hearing loss, including otosclerosis, Padget’s disease, and other conditions that cause defective bone development.
  2. Dr. Catherine Giacomini is a pharmacologist from the Department of Biopharmaceutical Sciences at UCSF. We are collaborating with Dr. Giacomini in exploring the mechanism(s) underlying hearing loss caused by platinum-based chemotherapies, investigating and designing novel otoprotective strategies for cisplatin therapy and examining the otoxicity of newly developed platinum compounds intended for use in chemotherapy.
  3. Drs. Saffeddine and Petit, from the department of Genetics and Physiology of Haring in the Pasteur Institute France. For several years we have collaborated with these investigators on several projects focusing on restoration of hearing and vestibular function using virally mediated gene therapy in mouse models of human genetic hearing loss -- the most recent of these being a model of Usher’s syndrome.

Techniques Used in the lab

  1. Specialized eletrophysiological recordings for hearing functions in mice including auditory brainstem responses (ABR), compound action potentials (CAP), distortion product oto-acoustic emissions (DPOAE), and contra-lateral suppression DPOAEs.
  2. Standard molecular biology techniques (e.g., molecular cloning, library preparations, RT-PCR, quantitative PCR etc.)
  3. Cochlea section and whole mount immunofuorescence and Histological methods
  4. Electron Microscopy (TEM, SEM)
  5. Viral and chemical delivery to the mouse inner ear (Postnatal day P1-3 and >P10)

Recent Significant Publications

  1. Akil O, Oursler AE, Fan K, Lustig LR. Mouse Auditory Brainstem Response Testing. Bio Protoc. 2016 Mar 20;6(6). pii: e1768. doi: 10.21769/BioProtoc.1768.
  2. Asoglu M, Aslan M, Imre O, Kivrak Y, Akil O, Savik E, Buyukaslan H, Fedai U, Altındag A. Mean platelet volume and red cell distribution width levels in initial evaluation of panic disorder. Neuropsychiatr Dis Treat. 2016 Sep 22;12:2435-2438. eCollection 2016.
  3. Jáuregui EJ, Akil O, Acevedo C, Hall-Glenn F, Tsai BS, Bale HA, Liebenberg E, Humphrey MB, Ritchie RO, Lustig LR, Alliston T. Parallel mechanisms suppress cochlear bone remodeling to protect hearing. Bone. 2016 Aug;89:7-15. doi: 10.1016/j.bone.2016.04.010. Epub 2016 Apr 13.
  4. Lustig LR, Alemi S, Sun Y, Grabowski G, Akil O. Role of saposin C and D in auditory and vestibular function. Laryngoscope. 2016 Feb;126(2):452-9. doi: 10.1002/lary.25479. Epub 2015 Jul 21.
  5. Akil O, Rouse SL, Chan DK, Lustig LR. Surgical method for virally mediated gene delivery to the mouse inner ear through the round window membrane. J Vis Exp. 2015 Mar 16;(97). doi: 10.3791/52187.

Additional Publications

Pudmed