Abstract

The long term objective of this proposal is to better understand the biochemical and biophysical changes that occur in the human lens with aging, and which ultimately lead to cataract. The proposed studies will be useful for achieving, in the future, the ultimate goal of significantly retarding the formation of aging-dependent cataract as well as eliminating the formation of secondary cataract which is commonly encountered following cataract surgery.
Specific Aim I : To characterize human lens eptithelial proteins: A key player in the maintenance of lens homeostasis is the epithelial layer. Freshly excised human epithelium which will be obtained following cataract surgery will be used. Measurements will be performed on individual epithelium. A portion of the epithelium will be use for enzyme activity determination, whereas the remaining piece will be used for determination of mRNA levels of the specific enzyme using PCR technology. The construction of human epithelial cDNA library will allow us to characterize various human epithelial proteins, and to find if there are lens- specific isoforms for any of the proteins.
Specific Aim II : To elucidate the newly discovered molecular chaperone function of alpha-crystallins: Molecular chaperones are very efficient in suppressing aggregation of denatured protein, a property the aging lens needs. Alpha-crystallin was found by us to be a molecular chaperone. This suggests that it has a dual role in the lens. One as a refractive element and a second one as a chaperone protecting other proteins from aggregation. The physical properties of alpha-crystallins will be studied by various techniques. The interaction of alpha-crystallin with other lens proteins such as beta, gamma, and MP-26 will be evaluated. The effects of aging and cataract on the chaperone function of alpha-crystallin will be examined in normal and cataractous human lenses.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37EY003897-14
Application #
2158956
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1981-08-01
Project End
1999-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
14
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
University of California Los Angeles
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095

  Publications

Wu, Mingxing; Zhang, Xinyu; Bian, Qingning et al. (2012) Oligomerization with wt ýýA- and ýýB-crystallins reduces proteasome-mediated degradation of C-terminally truncated ýýA-crystallin. Invest Ophthalmol Vis Sci 53:2541-50
Laganowsky, Arthur; Benesch, Justin L P; Landau, Meytal et al. (2010) Crystal structures of truncated alphaA and alphaB crystallins reveal structural mechanisms of polydispersity important for eye lens function. Protein Sci 19:1031-43
Huang, Qingling; Ding, Linlin; Phan, Kim B et al. (2009) Mechanism of cataract formation in alphaA-crystallin Y118D mutation. Invest Ophthalmol Vis Sci 50:2919-26
Chen, Ling; Holland, Gary N; Yu, Fei et al. (2008) Associations of seroreactivity against crystallin proteins with disease activity and cataract in patients with uveitis. Invest Ophthalmol Vis Sci 49:4476-81
Wang, Kaijun; Cheng, Catherine; Li, Lin et al. (2007) GammaD-crystallin associated protein aggregation and lens fiber cell denucleation. Invest Ophthalmol Vis Sci 48:3719-28
Ecroyd, Heath; Meehan, Sarah; Horwitz, Joseph et al. (2007) Mimicking phosphorylation of alphaB-crystallin affects its chaperone activity. Biochem J 401:129-41
Xia, Chun-hong; Liu, Haiquan; Chang, Bo et al. (2006) Arginine 54 and Tyrosine 118 residues of {alpha}A-crystallin are crucial for lens formation and transparency. Invest Ophthalmol Vis Sci 47:3004-10
Xia, Chun-hong; Cheng, Catherine; Huang, Qingling et al. (2006) Absence of alpha3 (Cx46) and alpha8 (Cx50) connexins leads to cataracts by affecting lens inner fiber cells. Exp Eye Res 83:688-96
Aquilina, J Andrew; Benesch, Justin L P; Ding, Lin Lin et al. (2005) Subunit exchange of polydisperse proteins: mass spectrometry reveals consequences of alphaA-crystallin truncation. J Biol Chem 280:14485-91
Treweek, Teresa M; Rekas, Agata; Lindner, Robyn A et al. (2005) R120G alphaB-crystallin promotes the unfolding of reduced alpha-lactalbumin and is inherently unstable. FEBS J 272:711-24

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