Peter S Steyger Lab
Lab phone: 503-494-2373
Location: HRC 4th Floor
Oregon Hearing Research Center
Oregon Health & Science University
3181 SW Sam Jackson Park Road
Portland, OR 97239
Drug trafficking across the blood-labyrinth barrier.
We are testing several hypotheses to identify which specific molecular mechanisms are involved in trafficking ototoxic drugs across the multi-layered blood-labyrinth barrier and into the cochlear fluids and hair cells. This project is described in the first half of the 30 minute presentation video below.
Aminoglycoside permeation of non-selective cation channels.
These lipophobic drugs readily enter specific cells, such as kidney proximal tubule cells and cochlear sensory hair cells. These cells take up aminoglycosides via (i) endocytosis, and (ii) more nefariously, via aminoglycoside-permeant cation channels such as the yet-to-be-identified mechanosensory transduction channels of sensory hair cells. In this project, we are identifying and validating a variety of candidate aminoglycoside-permeant cation channels and transporters expressed by kidney and cochlear cells.
How does inflammation potentiate ototoxicity?
Severe and life-threatening bacterial infections such as meningitis, or respiratory infections associated with cystic fibrosis, are urgently treated with aminoglycosides. These infections typically trigger severe systemic inflammatory responses. We recently demonstrated that systemic inflammation increases the cochlear uptake of aminoglycosides and exacerbates the ototoxicity of these drugs in preclinical models (Koo et al., 2015), and also in human subjects in a pilot study (Cross et al., 2015). These findings are described in the second half of the presentation video.
Thus, the permanent ototoxic side-effects associated with these life-saving drugs are potentiated by the endogenous inflammatory response triggered by the infection. We are currently planning a multi-institutional confirmatory observational study to validate our initial findings. These studies have the potential to further refine clinical interventions that require aminoglycosides to better preserve life-long auditory function. Furthermore, candidate otoprotective compounds to prevent aminoglycoside-induced ototoxicity should demonstrate efficacy in subjects with infection and/or inflammation, as well as healthy preclinical models.
Do genomic polymorphisms modulate aminoglycoside-induced ototoxicity?
Several recent studies by others have reported individuals with cystic fibrosis tend to fall in to two broad categories, one that experiences hearing loss after aminoglycoside exposure, and another that does not experience hearing loss, despite extensive exposure to aminoglycosides. This phenomena is typical of a genomic predisposition (or resistance) to cytotoxicity, and we are currently testing this hypothesis.
See the following 30-min video about Dr. Steyger's work.