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Overview

We have an active research group focused on the function and dysfunction of the inner ear.  Our goal is to understand how stimuli from the external world, such as sound, gravity and head movements are converted into electrical signals, how the information is encoded and how it is transmitted to the brain. Furthermore, we want to understand why genetic mutations cause hearing and balance dysfunction.  We plan to use this information to design novel therapeutic innervations for deafness and balance disorders.

Sensory transduction in the ear beings with deflection of mechanosensitive organelles that project from the apical surface of inner ear hair cells.  The exquisite sensitivity of the auditory system can initiate signals that encode the faint pizzicato of a classical violin.  Remarkably, auditory hair cells can also detect stimuli with amplitudes over a million times greater, and thus can signal the booming cannons of Tchaikovsky's 1812 Overture as well. This extraordinary dynamic range is the result of a sensory transduction process that utilizes several feedback mechanisms to precisely reposition and tune the mechanosensitive apparatus within the optimal range allowing detection of auditory stimuli that span the breadth of amplitudes and frequencies humans encounter daily.

Ongoing projects in the lab include the study of:

  • Mechanotransduction and adaptation in sensory hair cells
  • Firing properties of afferent neurons that relay information to the brain
  • Development of inner ear function
  • Novel gene therapy strategies to treat inner ear dysfunction

Background

Jeffrey Holt received a PhD from the University of Rochester in 1995.  He completed a postdoctoral fellowship with the Howard Hughes Medical Institute at Harvard Medical School in the laboratory of David Corey.  In 2001 Dr. Holt accepted a faculty position in the Department of Neuroscience at the University of Virginia.  In 2011 he returned to Harvard to join the Department of Otolaryngology, the F.M. Kirby Neurobiology Center and the Neurobiology Program at Boston Children’s Hospital. Dr. Holt was promoted to Professor of Otolaryngology at Harvard Medical School in 2016.

Selected Publications

  1. Gao X, Tao Y, Lamas V, Huang M, Yeh WH, Pan B, Hu YJ, Hu JH, Thompson DB, Shu Y, Li Y, Wang H, Yang S, Xu Q, Polley DB, Liberman MC, Kong WJ, Holt JR, Chen ZY, Liu DR. Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature. 2018
  2. Koehler KR, Nie J, Longworth-Mills E, Liu XP, Lee J, Holt JR, Hashino E. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat Biotechnol. 2017 Jun; 35(6):583-589.
  3. Pan B, Askew C, Galvin A, Heman-Ackah S, Asai Y, Indzhykulian AA, Jodelka FM, Hastings ML, Lentz JJ, Vandenberghe LH, Holt JR, Géléoc GS. Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat Biotechnol. 2017 Mar; 35(3):264-272.
  4. Corey DP, Holt JR. Are TMCs the Mechanotransduction Channels of Vertebrate Hair Cells? J Neurosci. 2016 Oct 26; 36(43):10921-10926.
  5. Liu XP, Koehler KR, Mikosz AM, Hashino E, Holt JR. Functional development of mechanosensitive hair cells in stem cell-derived organoids parallels native vestibular hair cells. Nature Com.. 7:11508, 2016
  6. Akyuz N, Holt JR. Plug-N-Play: Mechanotransduction Goes Modular. Neuron. 89(6):1128-30, 2016.
  7. Askew C, Rochat C, Pan B, Asai Y, Ahmed H, Child E, Schneider BL, Aebischer P, Holt JR. Tmc gene therapy restores auditory function in deaf mice. Science Translational Medicine. 7(295):295ra108, 2015.
  8. Géléoc GS, Holt JR. Sound strategies for hearing restoration. Science. 344(6184):1241062. 2014
  9. Pan B, Géléoc GS, Asai Y, Horwitz GC, Kurima K, Ishikawa K, Kawashima Y, Griffith AJ, Holt JR. TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron. 79(3):504-15, 2013.
  10. Kawashima Y, Géléoc GS, Kurima K, Labay V, Lelli A, Asai Y, Makishima T, Wu DK, Della Santina CC, Holt JR, Griffith AJ. Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J Clinical Investigation. 121(12):4796-809, 2011.