Molecular Genetics of the Inner Ear
Welcome to the Grillet Lab
POSTDOCTORAL SCHOLARS in Neurosciences- mechanobiology- electronic microscopy Stanford University School of Medicine Department of Otolaryngology The laboratory of Nicolas Grillet is recruiting two postdoctoral fellows to work on the molecular mechanisms of sound detection. The hair cells of the inner ear have a mechanotransduction organelle,......
We have received confirmation from the NIH that our application “High-resolution localization of the hair cell mechanotransduction channel components by immunogold-scanning electronic microscopy” will be financed for 2 years!...
KATHARINE WAS AWARDED THE DEAN’S FELLOWSHIP 2019-2020!!!...
Hearing loss is a major health concern for our societies. In the United States of America, 17% of the adult population suffers from some degree of hearing loss. In addition, the elderly population frequently experiences debilitating hearing difficulties, and sometimes balancing issues.
Our goal is to identify the comprehensive list of genes required for hearing and head motion detection, and ultimately characterize the function of these genes at the molecular level.
This will improve our understanding of the inner ear physiology, but also will help the diagnosis of patients affected by hearing loss.
The inner ear contains the sensory cells that detect sound and head motion, the hair cells. In mammals, these cells are generated during the mid-gestation and will never be replaced during the entire life. The hair cells are in constant activity and their dysfunction is a major cause of deafness and peripheral vestibular disorders: they are both the core and the Achilles’ heel of the system.
Hearing loss can result from exposure to excessive noise, chemicals and certain medications. However, susceptibility to deafness is generally dictated by genetic transmission. To this date, 136 human loci have been linked to hearing loss, but we know the corresponding affected genes for only 85 of them. These genes are very often required, directly or indirectly, for the proper hair cell function.
In order to identify these genes, we use mouse models either to precisely inactivate candidate genes (Reverse Genetics) or to generate randomly mutated animals and screen them for hearing or vestibular defects (Forward Genetics).
Using this later method, we identified the gene Loxhd1 as responsible for deafness in mice and humans (Grillet, AJHG, 2009), who are affected by a form of progressive hearing loss called DFNB77.
Differently from the sense of Vision, still little is known about Hearing and Balancing at their molecular level. This is due to the technical challenges associated with this organ: the paucity of the inner ear sensory cells, their inaccessibility and their fragility.
The inner ear is composed of two functional parts: the cochlea, which is the auditory organ, and the vestibule, organ responsible for head motion and balancing. In both parts, the sensory epithelia are composed of the sensory hair cells, called hair cells, always surrounded by supporting cells.
We want to characterize down to the molecular level the function of the cells that compose the inner ear, particularly the hair cells
The hair cells have different functions:
1) to detect the mechanical stimuli induced by sound, and
2) to transmit this information to the central nervous system through their synapses.
We are particularly interested in the organelle of mechanotransduction, the hair bundle. The hair bundle is located at the apical surface of the hair cells, consisting of a precise staircase arrangement of membrane protrusions filled with filamentous actin, bound to each other by extracellular linkages. Upon stimulation, force engages the bundle, and opening large conductance mechanically gated channels, generating the current that allows the sense of hearing and balancing. Cochlear hair bundles present different morphologies along the cochlea, differing from the elongated ones found in the vestibule.
We are interested in understanding the uniqueness of the hair bundles by identifying their key components and their functions.
In order to identify the key components of the stereocilia bundle we will be using different approaches such as mouse Genetics, Electronic Microscopy, Electrophysiology or Biophysics.
By using a mouse model, we have previously showed that the USH1C protein Harmonin is required for the proper sensitivity of the hair bundle to mechanical stimulation (Grillet et al., Neuron, 2009). More recently, we also have shown that the protein TMHS is associated with part of the mechanotransduction machinery and influences the mechano-channel properties (Xiong, Cell, 2012).
Post-Doctoral trainees :
ALIX TROUILLET : Post-Doctoral Fellow, Geneva
MATTIA CARRARO : Co-Founder at Science Meets Design Inc.
DILETTA POZZI : Research Scientist, SISSA, Italy
Undergraduate Students :
ELLEN OUYANG
MARY ALEKSEEVA
BINH NGUYEN
High School Student :
SELENA YUAN
SYDNEY CHEEK
A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58.
Lezirovitz K, Vieira-Silva GA, Batissoco AC, Levy D, Kitajima JP, Trouillet A, Ouyang E, Zebarjadi N, Sampaio-Silva J, Pedroso-Campos V, Nascimento LR, Sonoda CY, Borges VM, Vasconcelos LG, Beck RMO, Grasel SS, Jagger DJ, Grillet N, Bento RF, Mingroni-Netto RC, Oiticica J.
Hum Mol Genet. 2020 Jun 3;29(9):1520-1536.
Osmotic stabilization prevents cochlear synaptopathy after blast trauma.
Kim J, Xia A, Grillet N, Applegate BE, Oghalai JS.
Mechanosensory hair cells express two molecularly distinct mechanotransduction channels.
Wu Z*, Grillet N*, Zhao B, Cunningham C, Harkins-Perry S, Coste B, Ranade S, Zebarjadi N, Beurg M, Fettiplace R, Patapoutian A, Müller U.
Nat. Neurosci. 2017 Jan;20(1):24-33. * Shared first-authorship PubMed PDF
Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans.
Grillet N, Schwander M, Hildebrand MS, Sczaniecka A, Kolatkar A, Velasco J, Webster JA, Kahrizi K, Najmabadi H, Kimberling WJ, Stephan D, Bahlo M, Wiltshire T, Tarantino LM, Kuhn P, Smith RJ, Müller U.
2 positions are open for post-doctoral training or advanced undergraduate students
To apply contact Nicolas Grillet at ngrillet@stanford.edu
Otolaryngology Department
Stanford School of Medicine
Stanford University
340 Pasteur Drive
BioMedical Innovation (BMI)building
Lab: Room 1400
Office: Room 1654
Stanford, CA 94305
Office: (650) 497-9393
Lab: (650) 498-5229
Fax: (650) 721-2163
Otolaryngology Department
Stanford School of Medicine
Stanford University
1291 Welch Road
BioMedical Innovation (BMI)building
Lab: Room 1400, GRILLET LAB
Office: Room 1654
Stanford, CA 94305
Email: ngrillet@stanford.edu
Phone: (650) 497-9393
Fax: (650) 721-2163
Exploring Sounds and Science
(February 20th 2020, nightlife Noise Pop Fest Showcase)
Sometimes pictures are more telling than words to describe scientific experiments.
We present here some images from our research on the inner ear.
These pictures are copyright protected; please contact the lab to obtain permission for use.
HISTOLOGY
MOLECULAR
BIOLOGY
MOUSE GENETICS
FLUORESCENCE MICROSCOPY
SCANNING EM
TRANSMISSION
E M
BIOINFORMATICS
COVERS
We want to warmly thank the donors of the Stanford Initiative to Cure Hearing Loss for their support!!! Your participation makes a real difference for our endeavor.
If you want to foster our research, you too can become a contributor to the Grillet lab. Simply click the “Contribute” button below. In “Special Instructions/Other Designation” specify “Grillet lab”.
