Jeffrey R. Holt, PhD

Professor of Otolaryngology & Neurology
F.M. Kirby Neurobiology Center, Boston Children's Hospital
Jeff Holt Photo
jeffrey.holt@childrens.harvard.edu
Holt Laboratory Webpage

Projects in our lab focus on mechanotransduction or the conversion of mechanical signals into electrical signals in the inner ear.  The process underlies our senses of hearing and balance.  We have identified several proteins critical for mechanotransduction in the inner ear.  We are interested to determine the molecular structure and function of these proteins and understand why genetic mutations in these molecules lead to dysfunction.  Our ultimate goal is to provide a biophysical understanding for developing therapeutics to restore structure and function in the inner ears of patients with hearing and balance disorders.

 

Select Publications:

1: Marcovich I, Baer NK, Shubina-Oleinik O, Eclov R, Beard CW, Holt JR. Optimized AAV Vectors for TMC1 Gene Therapy in a Humanized Mouse Model of DFNB7/11.  Biomolecules.  2022 Jun 29;12(7):914. doi: 10.3390/biom12070914.

2: Shubina-Oleinik O, Nist-Lund C, French C, Rockowitz S, Shearer AE, Holt JR. Dual-vector gene therapy restores cochlear amplification and auditory sensitivity in a mouse model of DFNB16 hearing loss.  Sci Adv. 2021 Dec 17;7(51):eabi7629. doi: 10.1126/sciadv.abi7629.

3: Nist-Lund CA, Pan B, Patterson A, Asai Y, Chen T, Zhou W, Zhu H, Romero S, Resnik J, Polley DB, Géléoc GS, Holt JR. Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders.  Nat Commun. 2019 Jan 22;10(1):236. doi: 10.1038/s41467-018-08264-w.

4: Pan B, Akyuz N, Liu XP, Asai Y, Nist-Lund C, Kurima K, Derfler BH, György B, Limapichat W, Walujkar S, Wimalasena LN, Sotomayor M, Corey DP, Holt JR. TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells.  Neuron.  2018 Aug 22;99(4):736-753.e6. doi: 10.1016/j.neuron.2018.07.033.

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.  Nat Commun.  2016 May 24;7:11508.  doi: 10.1038/ncomms11508.

6: 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.  Sci Transl Med. 2015 Jul 8;7(295):295ra108.  doi: 10.1126/scitranslmed.aab1996.

7: Géléoc GS, Holt JR. Sound strategies for hearing restoration.  Science.  2014 May 9;344(6184):1241062. doi: 10.1126/science.1241062.

8: 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.  2013 Aug 7;79(3):504-15. doi: 10.1016/j.neuron.2013.06.019.