This year our laboratory has undergone several changes and made some interesting progress along several lines.

Anthony Peng, a postdoc in the lab is now an Assistant Professor at the University of Colorado. We are all proud to see his growth and are excited to see him flourish as an independent investigator. Before leaving, Anthony published a paper in the Journal of Neuroscience that demonstrated, for the first time, a role for the lipid bilayer in regulating hair cell mechanotransduction. This is an important and exciting new finding that opens the door to a new area for research. Given that the hair cell hair bundle, the site of mechanotransduction, is a major target for age, noise and many genetic forms of hearing loss, identifying regulatory pathways is important as it identifies potential new targets for intervention. Understanding the molecular components underlying how the lipid bilayer regulates mechanotransduction is a major area of research that postdocs Thomas Effertz and new postdoc Shefin George are exploring. We are in the process of developing a variety of new technologies in order to directly address these questions.

Aside from investigating the role of the lipid bilayer in regulating hair cell mechanotransduction, we recently published a paper demonstrating that sensory hair bundles have stereocilia that can move independently of each other. This work demonstrates that mammalian hair bundles are quite different than those from lower frequency hearing organs and also opens the door to new modes of regulating hair bundle stimulation. This is critically important work as hair bundle mechanics are a major target for disorders that lead to hearing loss and also because this lack of cohesiveness likely underlies many of the published differences in hair bundle responses to different modes of stimulation.

Alex Scharr, a senior graduate student in the laboratory is actively involved in trying to identify how hair bundle stimulation alters the mechanical response of the cell. We believe this work will help to answer the long term question of why some hair bundles are embedded in an overlying membrane and others are not.

Along with this approach Yanli Wang, a mechanical engineering graduate student, has created a new preparation where she can image at high speed (20-50,000 fps) the motion of hair bundles in situ, in response to a natural stimulation. Her work will resolve the long standing question of how hair bundles move in response to natural stimulation and will allow us to design new stimulating probes for in vitro experiments.

And finally, we have Gaby Steiner, an undergraduate Biology major, who recently competed for an internal BioX award and won first place in the summer research symposia contest, who is imaging in vivo, the structure of the living cochlea. This work builds on recently published collaborative work and will help inform on the forces acting upon the hair bundle in vivo.

Autefeh Sajjadi, a postbac in our laboratory has recently departed for medical school at Creighton University. We are all proud of her and hope she returns to continue the research that she was involved in. Autefeh began a project to study age related hearing loss (ARHL). We recently received funding from the National Institute of Aging as a joint grant to investigate the underlying factors involved in ARHL. Our hypothesis is that regardless of the molecular mechanism, hearing loss will occur by first effecting the most vulnerable pathway. We further hypothesize that this pathway involves the high threshold afferent fiber hair cell synapse and that it has been undetected to date because of the manner in which hearing tests are performed. Autefeh has begun these exciting experiments and we have a new lab member Noor Ali joining to take on this exciting project.

We recently published a paper demonstrating that we could create new aminoglycoside antibiotics that lose their ototoxic effects. This work is now funded by the NIDCD in a grant that is co-led by Alan Cheng and myself. We are fortunate to be able to expand our program by recruiting Mary O’Sullivan, a new postdoc, who is driving the work to derive the next generation of antibiotics. Along with Mary we have recruited Hasan DeMirci, an expert in X-ray crystallography and ribosome-aminoglycoside interactions, to aid us in drug design by pioneering new technology that allows direct visualization of drug ribosome binding at room temperature.

In addition, we now have Randy Lin, a postbac student and Adela Perez, a Stanford medical student are investigating the ototoxicity of newly isolated compounds in vitro.

And finally, Sanjay Malhotra has joined Bob Greenhouse as the chemists involved in designing and creating synthetic pathways for our new compounds. We are very excited that this strong team will develop new antibiotics that can replace those that result in ototoxicity.