Extracapsular cataract surgery leaves the lens capsule mostly intact, which permits implantation of an intraocular lens (IOL). This procedure often leaves behind epithelial cells in the remaining anterior and equatorial capsule, which in time, proliferate and migrate to the posterior capsule. This aberrant growth of epithelial cells, together with transdifferentiation into a mesenchymal phenotype (EMT), leads to posterior capsule opacification (PCO). PCO impairs vision and requires laser treatment for resolution. With the advent of newer and more refined IOLs, the incidence of PCO has decreased;however, a significant number of cataract patients return for PCO treatment. The increasing use of accommodative IOLs could cause the number of returning patients to increase because of the reduced barrier for epithelial cells. Despite many years of research, the biochemical mechanisms of PCO are not well understood. Glycation is a major chemical modifier of extracellular matrix proteins. The reaction occurs between protein amino groups and carbonyl compounds and leads to the formation of stable adducts on proteins, collectively known as Advanced Glycation Endproducts (AGEs). The lens capsule is a basement membrane secreted by epithelial cells, and like other basement membranes, it accumulates AGEs with age. Based on our preliminary data, we hypothesize that AGEs in capsule proteins hinder the adhesion and migration of epithelial cells and induce their transdifferentiation to a mesenchymal cell type. In this proposal, we plan to investigate the biochemical and molecular mechanisms by which AGEs play a role in PCO with three aims.
In Aim 1, we will determine the relationship between cataract and AGE content in human lens capsules.
In Aim 2, we will define the biochemical pathways by which capsule AGEs influence epithelial cell adhesion, proliferation, and migration, and then investigate alterations in cell signaling that are responsible for the aberrant behavior o lens epithelial cells.
In Aim 3, we will determine the effect of capsule AGEs on EMT in lens epithelial cells and explore the possibility of inhibiting PCO by blocking the interaction of AGE with its receptor on lens epithelial cells. Completion of these aims will uncover a mechanism of PCO, and will provide a foundation for the development of more effective therapies to prevent PCO.

Public Health Relevance

Posterior capsule opacification, which is also known as secondary cataract, is a common post-cataract surgery problem and requires additional treatment to correct the vision. We hypothesize the lens capsule proteins influence the onset of secondary cataracts. This project seeks to understand how changes in capsule proteins affect epithelial cell functions and their transformation into mesenchymal type cells during secondary cataract development and proposes to test a novel method to prevent secondary cataracts.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY022061-02
Application #
8600277
Study Section
Special Emphasis Panel (BVS)
Program Officer
Araj, Houmam H
Project Start
2013-02-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
$356,625
Indirect Cost
$131,625
Name
Case Western Reserve University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Raghavan, Cibin T; Smuda, Mareen; Smith, Andrew J O et al. (2016) AGEs in human lens capsule promote the TGFβ2-mediated EMT of lens epithelial cells: implications for age-associated fibrosis. Aging Cell 15:465-76
Panda, Alok Kumar; Nandi, Sandip Kumar; Chakraborty, Ayon et al. (2016) Differential role of arginine mutations on the structure and functions of α-crystallin. Biochim Biophys Acta 1860:199-210
Raghavan, Cibin T; Nagaraj, Ram H (2016) AGE-RAGE interaction in the TGFβ2-mediated epithelial to mesenchymal transition of human lens epithelial cells. Glycoconj J 33:631-43
Rakete, Stefan; Nagaraj, Ram H (2016) Identification of Kynoxazine, a Novel Fluorescent Product of the Reaction between 3-Hydroxykynurenine and Erythrulose in the Human Lens, and Its Role in Protein Modification. J Biol Chem 291:9596-609
Nahomi, Rooban B; Pantcheva, Mina B; Nagaraj, Ram H (2016) αB-crystallin is essential for the TGF-β2-mediated epithelial to mesenchymal transition of lens epithelial cells. Biochem J 473:1455-69
Nahomi, Rooban B; DiMauro, Michael A; Wang, Benlian et al. (2015) Identification of peptides in human Hsp20 and Hsp27 that possess molecular chaperone and anti-apoptotic activities. Biochem J 465:115-25
Smuda, Mareen; Henning, Christian; Raghavan, Cibin T et al. (2015) Comprehensive analysis of maillard protein modifications in human lenses: effect of age and cataract. Biochemistry 54:2500-7
Linetsky, Mikhail; Raghavan, Cibin T; Johar, Kaid et al. (2014) UVA light-excited kynurenines oxidize ascorbate and modify lens proteins through the formation of advanced glycation end products: implications for human lens aging and cataract formation. J Biol Chem 289:17111-23
DiMauro, Michael A; Nandi, Sandip K; Raghavan, Cibin T et al. (2014) Acetylation of Gly1 and Lys2 promotes aggregation of human γD-crystallin. Biochemistry 53:7269-82

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