Biology of Lens Intercellular Communication

University Of Chicago, Chicago IL

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Cataracts are the leading cause of blindness world-wide. Mutations of two genes that encode lens gap junction proteins (Cx46 and Cx50) are among the most frequent genetic causes of congenital cataracts. We have previously studied many of the human cataract-linked human Cx46 and Cx50 mutations using exogenous expression systems. Most frequently, mutants showed loss of function associated with cytoplasmic retention and/or impaired cellular trafficking. During the last grant period, we developed and characterized two lines of mice with mutations that mimic human cataract-associated lens connexin mutants (Cx50D47A/No2 and Cx46fs380). A common finding in both mouse lines is reduced levels of both mutant and wild type connexins even in heterozygous animals. We suspect that they are both degraded. The current project will use tissue culture, organ culture, and in vivo approaches to test the hypothesis (in each mouse model) that cataracts result from the combination of two mechanisms: 1: Expression of the mutant connexin triggers various cellular responses (that are initially compensatory) including connexin degradation and activation of the Unfolded Protein Response (UPR) that may have deleterious consequences after continuous activation. 2: The reduced connexin and gap junction abundance lead to alterations in intercellular communication, distribution of gap junction-permeant ions and molecules within the lens, and membrane structure. We will test interventions to restore connexin levels/localization or to block UPR activation and anticipate that they will improve connexin functions and may retard the progression of lens damage. Elucidating the process of cataractogenesis due to connexin mutations is likely to give insights into fundamental aspects of the pathogenesis of this disease.