Presbyopia and age-related cataracts (ARC) are two of the most common age-related ocular disorders, and there is no effective way to delay or prevent them. Continuous lens growth throughout life not only will increase the stiffness of lens to cause presbyopia but will also increase the distance for transport of nutrients, ions and water from peripheral metabolically active cells into interior metabolically inactive fibers, which likely impedes lens homeostasis to contribute to age-related cataract. It is unknown why lens equatorial epithelial cells continue to proliferate and differentiate into elongating fiber cells even after the lens reaches the appropriate size for focusing clear images onto the retina. Cell proliferation and differentiation are not required for maintaining the homeostasis or function of many other cell types including corneal endothelial cells, retinal neurons and retinal pigment epithelial cells in a mature eye. Perhaps inhibiting lens size increase after the lens reaches its appropriate size will effectively maintain lens homeostasis to delay presbyopia and age-related cataracts. However, such a strategy has never been tested due to a lack of appropriate way to selectively prevent mature lens growth without affecting early lens formation. Current knowledge about lens growth regulation is mainly from studies of early lens development. The regulation of lens growth in a mature lens after it is fully developed has been rarely studied. Thus, the primary goal of this project is to investigate the growth control mechanisms after the lens is fully developed. We have recently found that the aA-crystallin Y118D mutation selectively inhibits lens growth after the lens is fully developed. Mutant lenses display drastically reduced growth after weaning age and stop growing at the age of 8 weeks. We hypothesize that the gain-of-function aA-crystallin Y118D mutant protein selectively inhibits the proliferation and differentiation of lens epithelial cells and/or the elongation of newly differentiated fiber cells to reduce and stop the growth of a fully developed lens, and that such a selective inhibition depends on an altered level and/or function of aA-crystallin Y118D mutant proteins in lens cells. This research proposal will test this hypothesis and elucidate the molecular basis for how aA-crystallin Y118D mutant proteins with increased chaperone-like activity regulate the cellular and mechanical properties of lens epithelial cells. This information will be useful for developing a new strategy to inhibit size increase in mature lenses that may prevent presbyopia and/or delay age-related cataracts.

Public Health Relevance

Increased lens size contributes to presbyopia and age-related cataract. This project will investigate the mechanisms for how the aA-crystallin Y118D mutation selectively inhibits lens growth after the lens is fully developed. Anticipated results may be useful for developing a new strategy to inhibit lens size increase, thus delaying or preventing presbyopia and age-related cataract.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021519-03
Application #
8424292
Study Section
Special Emphasis Panel (ZRG1-ETTN-E (92))
Program Officer
Araj, Houmam H
Project Start
2011-03-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2013
Total Cost
$291,650
Indirect Cost
$101,650
Name
University of California Berkeley
Department
None
Type
Schools of Optometry/Ophthalmol
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Li, Jiawen; Li, Xiang; Mohar, Dilbahar et al. (2014) Integrated IVUS-OCT for real-time imaging of coronary atherosclerosis. JACC Cardiovasc Imaging 7:101-3
Du, Yongzhao; Liu, Gangjun; Feng, Guoying et al. (2014) Speckle reduction in optical coherence tomography images based on wave atoms. J Biomed Opt 19:056009
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, Gangjun; Chen, Zhongping (2013) Capturing the vital vascular fingerprint with optical coherence tomography. Appl Opt 52:5473-7
Kim, Chang Soo; Qi, Wenjuan; Zhang, Jun et al. (2013) Imaging and quantifying Brownian motion of micro- and nanoparticles using phase-resolved Doppler variance optical coherence tomography. J Biomed Opt 18:030504
Li, Jiawen; Ma, Teng; Jing, Joseph et al. (2013) Miniature optical coherence tomography-ultrasound probe for automatically coregistered three-dimensional intracoronary imaging with real-time display. J Biomed Opt 18:100502