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.

Public Health Relevance

The primary goal of this project is to identify and characterize new genetic factors that suppress the formation of cataract. The new information from this study will be important not only for understanding the mechanism that controls the severity and/or onset of nuclear cataracts but also for developing a new non-surgical strategy to prevent and/or delay cataract formation.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY013849-10
Application #
8297621
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
2002-02-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
10
Fiscal Year
2012
Total Cost
$383,750
Indirect Cost
$133,750
Name
University of California Berkeley
Department
Type
Schools of Optometry/Ophthalmol
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Wang, Dong; Wang, Eddie; Liu, Kelsey et al. (2017) Roles of TGF? and FGF signals during growth and differentiation of mouse lens epithelial cell in vitro. Sci Rep 7:7274
Wang, Eddie; Geng, Andrew; Seo, Richard et al. (2017) Knock-in of Cx46 partially rescues fiber defects in lenses lacking Cx50. Mol Vis 23:160-170
Cheng, Catherine; Fowler, Velia M; Gong, Xiaohua (2017) EphA2 and ephrin-A5 are not a receptor-ligand pair in the ocular lens. Exp Eye Res 162:9-17
Wang, Eddie; Geng, Andrew; Maniar, Ankur M et al. (2016) Connexin 50 Regulates Surface Ball-and-Socket Structures and Fiber Cell Organization. Invest Ophthalmol Vis Sci 57:3039-46
Xia, Chun-hong; Liu, Haiquan; Cheung, Debra et al. (2015) NHE8 is essential for RPE cell polarity and photoreceptor survival. Sci Rep 5:9358
Hitomi, Masahiro; Deleyrolle, Loic P; Mulkearns-Hubert, Erin E et al. (2015) Differential connexin function enhances self-renewal in glioblastoma. Cell Rep 11:1031-42
Zhu, Yanan; Yu, Hao; Wang, Wei et al. (2014) A novel GJA8 mutation (p.V44A) causing autosomal dominant congenital cataract. PLoS One 9:e115406
Xia, Chun-hong; Lu, Eric; Zeng, Jing et al. (2013) Deletion of LRP5 in VLDLR knockout mice inhibits retinal neovascularization. PLoS One 8:e75186
Cheng, Catherine; Ansari, Moham M; Cooper, Jonathan A et al. (2013) EphA2 and Src regulate equatorial cell morphogenesis during lens development. Development 140:4237-45
Liu, Zhenzhen; Taylor, Allen; Liu, Yizhi et al. (2012) Enhancement of ubiquitin conjugation activity reduces intracellular aggregation of V76D mutant ?D-crystallin. Invest Ophthalmol Vis Sci 53:6655-65

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