Research

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Jeffrey  Holt, PhD

Jeffrey Holt
Lab:
Holt/Geleoc Laboratory
Research Center:
F.M. Kirby Neurobiology Center
Program:
Neurobiology Program
Department:
Neurology Research
Hospital Title:
Research Associate in Otolaryngology and Neurobiology
Academic Title:
Associate Professor of Otology and Laryngology, Harvard Medical School
Research Focus Area:
Molecular basis of sensory signals in hearing and deafness
Contact:
617-919-3574
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Research 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. 

About Jeffrey Holt

Jeffrey Holt received a Ph.D. 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 he accepted a faculty position in the Department of Neuroscience at the University of Virginia.  In 2011 Dr. Holt returned to Harvard to join the Department Otology and Laryngology and the Program in Neurobiology at Children’s Hospital. 

Key Publications

  • Y. Kawashima, G. S. G. Géléoc, K. Kurima, V. Labay, A. Lelli, Y. Asai, T. Makishima, D. K. Wu, C. C. Della Santina, J.R. Holt and A.J. Griffith. Mechanotransduction in Mouse Inner Ear Hair Cells Requires Transmembrane Channel-Like Genes 1 and 2, JCI. 121(12):4796-809,  2011

  • Horwitz GC, Risner-Janiczek JR, Jones SM, Holt JR.  HCN Channels Expressed in the Inner Ear Are Necessary for Normal Balance Function.J Neurosci. 31:16814-25. 2011

  • N. Charizopoulou, A.Lelli, M. Schraders, K. Ray, R.J.C. Admiraal, H.R. Neely, J.R. Latoche, J.K. Northup, H. Kremer, J.R. Holt, and K. Noben-Trauth.  Mutations in the PDZ domain containing protein Gipc3 cause progressive sensorineural degeneration (ahl5 and jams1) in mice and recessive hearing impairment in humans.  Nature Com.10.1038/ncomms1200,2011.

  • A. Lelli, P. Kazmierczak, Y.Kawashima, U. Müller and J.R. Holt. Development and Regeneration of Sensory Transduction in Auditory Hair Cells Requires Functional Interaction Between Cadherin-23 and Protocadherin-15.  J. Neurosci. 30:11259-69, 2010.

  • B.W. Kesser,G.T. Hashisaki, K. Fletcher, H. Eppard and J.R. Holt. An in vitro model system to study gene therapy in the human inner ear. Gene Therapy. 14:1121-31,2007. 

  • J.R. Holt, E.A. Stauffer, D. Abraham, G.S. Géléoc. Dominant-negative inhibition of M-like potassium conductances in hair cells of the mouse inner ear. J Neurosci 27:8940-51, 2007

  • E.A. Stauffer, J. Scarborough, M. Hirono, E.D. Miller, K. Shah, J.A. Mercer, J. R. Holt,  P. G. Gillespie. Fast Adaptation in Vestibular Hair Cells Requires Myosin-1c Activity.  Neuron 47:541-553, 2005.

  • G.S.G. Géléoc and J.R. Holt. Developmental acquisition of sensory transduction in hair cells of the mouse inner ear.  Nature Neurosci 6:1019-20, 2003.

  • J.R. Holt, S.K.H. Gillespie, D.W. Provance, K. Shah, K.M. Shokat, D.P. Corey, J.A. Mercer, P.G. Gillespie. A chemical-genetic strategy implicates myosin-1C in adaptation by hair cells.  Cell108: 371-381, 2002.     

For a complete list of Dr. Holt's publications, click here.

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Related Laboratory

Holt/Geleoc Laboratory

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RELATED RESEARCH CENTER

F.M. Kirby Neurobiology Center

The Program in Neurobiology at Boston Children's Hospital, including the F.M. Kirby Neurobiology Center, is the largest basic neuroscience research enterprise at a U.S. hospital. It incorporates basic and translational neuroscience research, focusing primarily on developmental neurobiology.

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