Research Overview
Biology of Hair Cell Death
Death of sensory hair cells is the underlying cause of the majority of hearing losses and balance disorders. This research program focuses on the mechanisms of hair cell death and on the discovery of genes and drugs that protect hair cells. Hair cells die in response to a number of insults, including aging, noise trauma, and exposure to certain therapeutic drugs (including aminoglycoside antibiotics and the anti-cancer drug cisplatin). We now understand that hair cell death in response to most (or all) of these signals is an active process that is modulated by genetic activity and modulation of metabolic regulatory pathways in the hair cells and surrounding tissues. The goals of our work are to understand the cascade of cellular and molecular events involved in determining if challenged hair cells survive or die, and to design therapeutic drugs aimed at preventing hair cell death.
Several approaches are used in the laboratory to examine hair cell responses to ototoxic events. We use in vivo and in vitro preparations of mouse and chick inner ear and zebrafish lateral line hair cells to examine cellular pathways that are activated or inhibited during ototoxic drug-induced hair cell death.
Recently, we have used the zebrafish lateral line as a screening platform to discover genes and new drugs that effectively modulate the susceptibility of hair cells to damaging agents. In one case, we discovered a highly effective small drug-like molecule that powerfully inhibits aminoglycoside-induced hair cell death in zebrafish and hearing loss in rats.
Medicinal Chemistry was used to create several hundred analogs that were tested and assessed for drug properties, leading to a new drug under development for clinical trials. This “lead” compound proved highly effective for preventing hearing loss in rats receiving large doses of aminoglycoside, is very safe and has outstanding pharmacological properties. Oricula Therapeutics LLC , was established in Seattle to bring this drug to clinical trials. Future translational studies will examine the efficacy of our new drug candidates to prevent other forms of hearing and balance disorders.
Ontogeny of the Vertebrate Sensory Processes
