Deafness is the most common form of sensory impairment in humans and is frequently progressive in nature, but little is known about the molecular pathogenesis of the disease. Likewise, the mechanisms that control the development and function of auditory hair cells and neurons are poorly defined. A recent ENU mutagenesis screen has revealed that certain mutations in the genes for Pejvakin, Loxhd1, and Cdh23 cause progressive hearing loss in mice and humans. Pejvakin is a founding member of a novel gene family, the gasdermins. Different mutations in pejvakin can lead either to hair cell dysfunction or defects in spiral ganglion neurons indicating a role of pejvakin in the communication of hair cells with neurons. Pejvakin is a close homolog of the gasdermin DFNA5, and mutant alleles of pejvakin and DFNA5 can both cause progressive hearing loss. This suggests that the two proteins, as well as other gasdermins, may act in a similar molecular pathway that is important in both hair cells and neurons. To further define the mechanisms that control auditory processing we propose to (i) use genetic and biochemical approaches to study the cellular function of gasdermins, to (ii) identify interacting proteins, to (iii) design strategies to analyze their in vivo function in the auditory system, and to (iv) examine in the established ENU mutant lines whether different genetic forms of progressive hearing loss share a common pathophysiological pathway in hair cell and neuronal degeneration. In the long run, I will extend these studies extended to other genes including those that we are still identifying in the context of the ongoing genetic screen.