Deafness is an extremely common and disabling disorder affecting 1 in 1000 newborns in the US, with half of these cases being of genetic origin. Genetic defects are also important for progressive and age-related hearing loss, which significantly impair the quality of life of a large fraction of the aging population. Despite its clinical importance, the molecular pathogenesis of progressive hearing loss is not well understood. We and others have linked mutations in DFNB59 (encoding pejvakin) and DFNA5, two members of the gasdermin family of genes, to progressive hearing loss in humans. Depending on the type of mutation DFNB59 patients develop either progressive hearing loss with cochlear dysfunction or non-progressive auditory neuropathy. However, the precise site of the lesion underlying hearing loss and the physiological function of pejvakin and DFNA5 in the inner ear are still unknown. We hypothesize that these gasdermins regulate a cytoskeleton-associated signaling pathway at the stereocilia base that is important for the differentiation and survival of hair cells. In our preliminary data, we have generated a pejvakin conditional allele in mice and show that pejvakin regulates hair cell function in a cell-autonomous manner. We have employed immunohistochemical and hair cell transfection techniques and identified a unique subcellular distribution of pejvakin and DFNA5 at the base of the hair bundle consistent with a role for these proteins in the assembly or function of stereociliary rootlets. In addition, we have uncovered novel binding partners for gasdermins that are key components of signaling pathways that regulate cytoskeletal dynamics.
In Aim 1, we will analyze the physiological function of pejvakin further to determine the extent to which it regulates the function of sensory hair cells and neurons.
In Aim 2, we will determine the molecular determinants of gasdermin targeting in hair cells and the relevance of this process to progressive hearing loss.
In Aim3, we will characterize the biochemical pathways by which these gasdermins regulate hair cell function and determine the extent to which they modulate the organization of actin and microtubule cytoskeleton networks. The proposed studies will evaluate new in vivo models for progressive hearing loss, provide a deeper understanding of the molecular pathways in which gasdermins act, and provide important clues to the development of novel therapeutic strategies to prevent or treat hearing loss.

Public Health Relevance

1 in 10 Americans suffers from hearing loss that impairs their ability to perceive speech. The progressive forms of hearing loss are extremely prevalent in the adult population, but comparatively little is known about the underlying disease mechanisms. The proposed research examines the role of two members of the recently discovered gasdermin gene family in the pathogenesis of progressive hearing loss, and focuses on devising novel genetic models, cellular systems, and therapeutic strategies to tackle this important disease.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Auditory System Study Section (AUD)
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Freeman, Nancy
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Rutgers University
Anatomy/Cell Biology
Schools of Arts and Sciences
United States
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Kazmierczak, Marcin; Kazmierczak, Piotr; Peng, Anthony W et al. (2017) Pejvakin, a Candidate Stereociliary Rootlet Protein, Regulates Hair Cell Function in a Cell-Autonomous Manner. J Neurosci 37:3447-3464
Harris, Suzan L; Kazmierczak, Marcin; Pangrši?, Tina et al. (2017) Conditional deletion of pejvakin in adult outer hair cells causes progressive hearing loss in mice. Neuroscience 344:380-393
Kazmierczak, Marcin; Harris, Suzan L; Kazmierczak, Piotr et al. (2015) Progressive Hearing Loss in Mice Carrying a Mutation in Usp53. J Neurosci 35:15582-98