Connexin 26 (Cx26) is a member of a widely expressed family of proteins that form intercellular transmembrane channels or gap junctions.  Pathogenic mutations in the Cx26 gene have been identified in both autosomal dominant and recessive forms of non- syndromic hereditary hearing impairment (NHHI).  Mutations within Cx26 may account for 20 percent of all childhood deafness with a carrier rate as high as 2.8 percent.  Although, Cx26 mutations have been identified in humans, naturally occurring mutations of the Cx26 have not been detected in animal models.  Development of an animal model of Cx26 dysfunction has been attempted using gene knockout technology.  However, mice homozygous for targeted deletion of Cx26 die in utero, thus precluding analysis of Cx26 dysfunction in the adult.  As a first step towards deciphering the role of Cx26 in hearing, this study will test the hypothesis that constitutive expression of Cx26 is required for auditory function in an adult animal and thus transient disruption of its function would result in transient hearing impairment.  This hypothesis will be tested through the development and characterization of two separate animal models of Cx26 dysfunction, using established procedures that will sidestep the developmental restrictions upon Cx26 expression.  The common principle that underlies induction of Cx26 dysfunction in the proposed animal models is the introduction of a dominant negative allele that is extra- chromosomal or stably integrated and subsequent in vivo expression to nullify protein product of the endogenous wild type Cx26 allele.  The transgene will be introduced locally within the cochlear of an adult rat using cationic liposomes or as an inducible, stably integrated transgene in a transgenic mouse.  In vivo expression of the extra-chromosomal or stably integrated transgene will be followed by physiological and histopathological analysis of the inner ear.  The development and characterization of these animal models with Cx26 dysfunction will contribute significantly towards understanding the role of Cx26 in hearing under normal and pathologic conditions.