Research
If you have questions about these or
any other projects please feel free to email
Jeff Holt (jeffrey.holt-AT-childrens.harvard.edu) or
Gwen Géléoc (gwenaelle.geleoc-AT-childrens.harvard.edu)
Structure and Function of TMCs in Inner Ear Hair Cells
A major focus of work in the lab over the past 20 years has been identification of molecules and fundamental mechanisms of sensory transduction in auditory and vestibular hair cells. We aim to understand how hair cells convert information carried in sound and head movements into electrical signals that are transmitted to the brain. Our lab identified that TMC1 and TMC2 form the core of the mechanosensory transduction channels in vertebrate hair cells. A large body of evidence from our lab and others now supports this conclusion. For more information see: Kawashima et al., 2011; Pan et al., 2013; 2018; Lee et al., 2021; Ratzan et al., 2024; Holt et al., 2024.
Inner Ear Gene Therapy
We pioneered inner ear gene transfer, beginning nearly 25 years ago (Holt et al., 1999). Our lab continues to develop, innovate and discover viral vectors, promoters and DNA coding sequences for optimized delivery to the various cell types of the inner ear. In a series of recent publications we used viral gene delivery to restore auditory function in models of human deafness. In particular, we focused on the hearing loss genes TMC1 and STRC and others. See Holt et al., 1999; Holt, 2002; Pan et al., 2017; Nist-Lund et al, 2019; Lee et al., 2020;2021; Marcovich et al., 2022; Ratzan et al., 2024.
Usher Syndrome Therapies
Usher syndrome is the lead cause of combined deaf-blindness. Genetic variants in any of ten different genes can cause Usher syndrome. Our lab is developing novel therapeutics that target five different Usher genes. For more information see: Pan et al., 2017; Lentz et al., 2020; Geleoc & El-Amraoui, 2020; Mauriac & Geleoc, 2021.
Novel Mechanosensitive Channels
The largest family of mechanosensitive channels includes TMCs, OSCAs (from plants) and TMEM63s (animals). Recently we’ve taken up an interest in the structure and function of the TMEM63 proteins. TMEM63B is expressed in hair cells and causes deafness when genetically deleted. We used Cryo-EM to solve the structure of TMEM63A and B and find they function as monomeric mechanosensitive channels. In humans, genetic variants in TMEM63 genes cause a range of neurodevelopmental disorders. See Zheng et al., 2023 for more info.