Project Summary Predisposed genetic variance and life-long metabolic and environmental stresses can impair lens homeostasis and contribute to age-related cataracts. Inadequate knowledge about genetic and environmental etiology of cataractogenesis hinders the development of non-surgical approaches to effectively delay or prevent age-related cataracts. Decades of studies have led to the identification of many gene mutations that cause hereditary cataracts. However, there has not been much progress in finding genetic modifiers that influence the severity and/or occurrence of cataracts. Identification of any cataractous genetic modifiers will be important for understanding the pathological progression of cataract formation and for developing an alternative non-surgical treatment that is currently unavailable to prevent or delay age-related cataracts. This project aims to identify the genetic modifiers that suppress nuclear cataract formation by using mouse genetic models. Lens connexin gene mutations cause cataracts in humans and in mice. Previous studies have demonstrated that the genetic background of different inbred strains influences the severity of nuclear cataracts caused by connexin mutations. Using a novel strategy, a combination of a genome-wide linage analysis of quantitative trait loci (QTLs), chromosome substitution by homologous counterparts from inbred strains and identification of SNPs from candidate genes, we have genetically dissected the complex traits for nuclear cataracts in connexin knockout mice. We have identified a semi-dominant suppressor of nuclear cataracts that located in a 2 million base pair interval on chromosome 7. The presence of this genetic modifier prevents dense nuclear cataracts in connexin mutant mice. After searching the polymorphic differences in the coding region and measuring the lens expression of a list of genes in this interval, we have selected 5 candidate genes. The primary goal of this project is to determine which candidate gene functions as a semi-dominant suppressor and to investigate the molecular basis for the prevention of nuclear cataracts. Moreover, we will continue to identify additional new genetic modifiers that suppress cataractogenesis. The information will be important for developing a new strategy to effectively prevent or delay nuclear cataracts, which account for about one-third of age-related cataracts.