[et_pb_section fullwidth=”on” specialty=”off”][et_pb_fullwidth_slider admin_label=”Fullwidth Slider” show_arrows=”on” show_pagination=”on” auto=”off” parallax=”off” parallax_method=”off” module_id=”interior”][et_pb_slide background_image=”https:\/\/depts.washington.edu\/cfrtc\/wp-content\/uploads\/2014\/12\/microscope.jpg” background_color=”#ffffff” alignment=”center” background_layout=”dark” \/][\/et_pb_fullwidth_slider][\/et_pb_section][et_pb_section][et_pb_row][et_pb_column type=”1_4″][et_pb_sidebar admin_label=”Fellowships Sidebar” orientation=”left” area=”et_pb_widget_area_11″ background_layout=”light” \/][\/et_pb_column][et_pb_column type=”3_4″][et_pb_text admin_label=”Current Fellow Bellairs” background_layout=”light” text_orientation=”left”]<\/p>\n
Fellow: Joseph Bellairs, MD<\/a> Mentor: David Rabile, PhD<\/a> Aminoglycoside antibiotics are standard of care for life-threatening sinopulmonary infections in cystic fibrosis, however this class of antibiotics is exceptionally toxic to inner ear mechanosensory hair cells. Hair cells contain a specialized mechanoelectrical transduction (MET) apparatus responsible for translating sound and head movements into nerve impulses, but this unique system also renders hair cells sensitive to off-target effects of aminoglycosides and other therapeutics. Hair cell death leads to irreversible hearing loss, and outside of avoidance there are no reliable strategies to prevent aminoglycoside-induced hearing loss. ORC-13661 is a novel therapeutic that protects inner ear hair cells from aminoglycoside-induced toxicity and preserves hearing in preclinical animal models. Clinical evaluations of ORC-13661 are underway, however because this drug was discovered through a phenotypic screen its mechanism and molecular target remain unknown. Based on recent work, we hypothesize that ORC-13661 blocks MET-dependent uptake of aminoglycosides in hair cells. I propose using a chemical toolbox of photoreactive and biotinylated ORC-13661 analogues to test this hypothesis and identify the molecular target responsible for hearing protection. I will first use these analogues to localize the molecular target in zebrafish and mammalian hair cells. I will then use these analogues to covalently bind, isolate, and identify candidate target proteins with tandem mass spectrometry. Putative targets will be confirmed and characterized using CRISPR-based mutagenesis to generate null mutants. The results from these studies will facilitate the ongoing translation of ORC-13661 in clinical trials and expedite the development of future drugs and therapeutic strategies to prevent hearing loss.<\/p>\n [\/et_pb_text][\/et_pb_column][\/et_pb_row][\/et_pb_section]<\/p>\n","protected":false},"excerpt":{"rendered":" Fellow: Joseph Bellairs, MD Mentor: \u00a0David Raible, PhD P.I.: Ian de boer, MD<\/a>
\nOtolaryngology<\/p>\n
\nProfessor,\u00a0Biological Structure<\/p>\n
\nOtolayrngology<\/p>\n
\nProfessor, Biological Structure<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_et_pb_use_builder":"on","_et_pb_old_content":"
Associate Professor of Medicine
Nephrology<\/p>