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Hearing and deafness: molecular mechanisms and therapeutic approaches

Hearing impairment is the most common sensory deficit among the human population, affecting more than 400 million people worldwide (http://www.who.int/mediacentre/factsheets/fs300/en/). Deafness may occur at any age with any degree of severity. About 1 out of every 700 children born with a detectable level of hearing loss or deafness. Approximately one in three people over the age of 65 has hearing impairment.

Hearing loss threatens personal autonomy resulting in major difficulties in daily life and, ultimately, social isolation and depression.

In contrast to the conductive hearing loss, there are no effective treatments for sensorineural forms of hearing loss (SNHLs; eg. aminoglycoside (AG) antibiotic-induced hearing loss, noise-induced hearing loss (NIHL) and age-related hearing loss (AHL), except for symptomatic approaches with moderate efficacy. Tools to prevent and cure hearing impairment are absent, mainly due to insufficient knowledge of the basic molecular mechanisms of hearing, the defective mechanisms and endogenous protective factors in various sensorineural forms of deafness.

Our laboratory investigates the physiology of hearing and pathophysiology of SNHLs by fluorescent functional imaging ex vivo, in addition, testing potential otoprotective drug candidates in vivo against SNHLs by objective hearing tests (ABR: Auditory Brainstem Response; OAE: otoacoustic emission). Measurements are performed on wild-type and genetically engineered mice.

Our mission is to support and accelerate drug development in the field of SNHLs by identifying new drug targets and setting up preclinical in vivo models with high translational and predictive values.

We have research contracts with pharmaceutical companies and cooperate with the ENT Department of Semmelweis University.

Group leader: Zelles Tibor, MD, Phd, associate professor (Google Scholar)

Group Members:

  • Eszter Berekméri, PhD student
  • Viktória Humli, PhD student
  • Judit Szepesy, PhD student

Main research areas:

  • In vivo
    • Drug therapy for the most common forms of SNHLs (aminoglycoside antibiotic-induced hearing loss, noise-induced hearing loss and age-related hearing loss)

 Figure 1. Auditory Brainstem Response setup and the most common experimental mouse strains

Figure 2. „Noise box” and the effect of a single noise exposure on hearing thresholds

  • Ex vivo
    • Study of Ca2+ signaling and purinerg transmission in the supporting cells of the organ of Corti
    • Examine changes in purinerg signaling due to noise exposure
    • Determine the role of supporting cells in cochlear amplification

Figure 3. A) Fluorescence microscope B) Oblique illuminated images of dissected mature mouse cochlea (hemicochlea preparation) and the organ of Corti; fluorescence image of a Deiters’ cell

Acquirable skills:

  • scientific mindset
  • clinically oriented basic research
  • design of experiments
  • drug treatment of animals
  • fluorescence microscopy skills
  • fluorescent staining techniques
  • data analysis and presentation

Achievements of undergrad and postgrad students:

  • Deák Orsolya, Semmelweis University Students’ Scientific Association (TDK) Conference, Budapest, Hungary, 2018, 1st price and OTDK candidate
  • Szepesy Judit, FAMÉ conference, Pécs, Hungary, 2016, Poster Special Award
  • Berekméri Eszter, Semmelweis University Students’ Scientific Association (TDK) Conference, Budapest, Hungary, 2015, 1st price
  • Dienes Tamás, XXXII. OTDK, Budapest, Hungary, 2015, 2nd price
  • Dienes Tamás, Semmelweis University Students’ Scientific Association (TDK) Conference, Budapest, Hungary, 2015, 1st price
  • Humli Viktória, Hungarian Physiological Society Forum, Szeged, Hungary, 2015, Poster Award
  • Humli Viktória, Hungarian Society for Experimental and Clinical Pharmacology Forum, Velence, Hungary, 2015, Poster Section 3rd price
  • Humli Viktória, Semmelweis University PhD Scientific Days, Budapest, Hungary, 2014, Poster Section 1st price
  • Sahin-Tóth Judit, Semmelweis University Students’ Scientific Association (TDK) Conference, Budapest, Hungary, 2014, Boehringer Ingelheim price and OTDK candidate

References:

  1. Berekméri E, Deák O, Téglás T, Sághy É, Horváth T, Aller M, Fekete Á, Köles L, Zelles T. (2019); Targeted single-cell electroporation loading of Ca2+ indicators in the mature hemicochlea preparation. Res. 371:75-86
  2. Horvath T, Polony G, Fekete A, Aller M, Halmos G, Lendvai B, Heinrich A, Sperlagh B, Vizi ES, Zelles T (2016). ATP-Evoked intracellular Ca2+ signaling of different supporting cells in the hearing mouse hemicochlea. Res., 41(1): 364-375.
  3. Köles L, Kató E, Hanuska A, Zádori ZS, Al-Khrasani M, Zelles T, Rubini P, Illes P (2016). Modulation of excitatory neurotransmission by neuronal/glial signalling molecules: interplay between purinergic and glutamatergic systems. Purinergic Signal., 12(1): 1-24.
  4. Delmaghani S, Defourny J, Aghaie A, Beurg M, Dulon D, Thelen N, Perfettini I, Zelles T, Aller M, Meyer A, Emptoz A, Giraudet F, Leibovici M, Dartevelle S, Soubigou G, Thiry M, Vizi ES, Safieddine S, Hardelin JP, Avan P, Petit C (2015). Hypervulnerability to sound exposure through impaired adaptive proliferation of peroxisomes. Cell, 163(4): 894-906.
  5. Polony G, Humli V, Ando R, Aller M, Horvath T, Harnos A, Tamas L, Vizi ES, Zelles T (2014). Protective effect of rasagiline in aminoglycoside ototoxicity. Neuroscience, 265: 263-273.
  6. Lendvai B., Halmos G.B., Polony G., Kapocsi J., Horváth T., Aller M., Vizi E.S., Zelles T. (2011). Chemical neuroprotection in the cochlea: the modulation of dopamine release from lateral olivocochlear efferents. Int., 59(2):150-8.
  7. Doleviczényi Z., Vizi E.S., Gacsályi I, Pallagi K., Volk B., Hársing L.G. Jr., Halmos G., Lendvai B., Zelles T. (2008). 5-HT(6/7) Receptor Antagonists Facilitate Dopamine Release in the Cochlea via a GABAergic Disinhibitory Mechanism. Neurochem Res., 33, 2364-2372.
  8. Halmos G., Horváth T., Polony G., Fekete A., Kittel A., Vizi E.S., van der Laan B.F., Zelles T., Lendvai B. (2008). The role of N-methyl-D-aspartate receptors and nitric oxide in cochlear dopamine release. Neuroscience, 154, 796-803.
  9. Doleviczényi Z., Halmos G., Répássy G., Vizi E.S., Zelles T., Lendvai B. (2005). Cochlear dopamine release is modulated by group II metabotropic glutamate receptors via GABAergic neurotransmission. Lett., 385, 93-98.
  10. Halmos G., Doleviczényi Z., Répássy G., Vizi E.S., Lendvai B., Zelles T. (2005). D2 autoreceptor inhibition reveals oxygen-glucose deprivation induced release of dopamine in guinea-pig cochlea. Neuroscience, 132, 801-809.