Sight is our most valued sense. Cataract, or opacification of the lens afflicts virtually all the elderly and surgical extraction of the opacified lens is the most commonly performed surgery, accounting for among the largest line items in our Medicare budget. Fortunately, there is a successful procedure for removing cataracts. Unfortunately, the success is of limited duration because cells grow in the lens capsular bag that remains after cataract surgery causing re-opacification or "secondary cataract." It is essential to discover means to extend the duration of lens clarity after surgery and it would also be of invaluable benefit to delay cataract formation initially. To accomplish these objectives it is essential to understand how cell proliferation and differentiation are controlled in the lens. Cataract is due in part to production of abnormal genes and proteins. The ubiquitin proteolytic pathway (UPP) controls the expression of many genes and the levels of many proteins. We have shown that alteration of components of the UPP result in abnormal lens cell proliferation, differentiation and cataracts. Our findings clearly demonstrate a critical role for a fully functional UPP in regulation of lens formation, including cell proliferation and differentiation. There are many components to a ubiquitin pathway. Identifying essential components of UPPs and elucidating their function will identify specific molecules, the activity of which, if controlled, can be used to regulate proliferation and differentiation. The research proposed herein will identify functions of ubiquitin per se, and specific controllers (UbcH3, 7, 10) of lens cell proliferation and differentiation. In accomplishing these objectives we will identify a myriad of new targets for pharmacologic intervention to delay formation of secondary cataract. Importantly, each of our hypotheses is testing a fundamental novel concept. Since much about the UPP is similar in many types of cells and tissues, the information we gather will provide understanding of how this pathway works in many other types of cells and tissue. Thus, our research will also inform about targets which should provide new therapeutics for many other tissues, in addition to lens, where controlled proliferation is desirable. This includes cornea, trabecular meshwork, retina and many cancers.

Public Health Relevance

Sight is our most valued sense. Cataract, or opacification of the lens afflicts virtually all the elderly and surgical extraction of the opacified lens is the most commonly performed surgery, accounting for among the largest line items in our Medicare budget. Unfortunately, the success of lens replacement surgery is of limited duration because of "secondary cataract." We will identify a myriad of new targets for pharmacologic intervention to delay formation of secondary cataract.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013250-11
Application #
8228066
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
2001-04-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
11
Fiscal Year
2012
Total Cost
$448,919
Indirect Cost
$164,793
Name
Tufts University
Department
Nutrition
Type
Organized Research Units
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Shang, Fu; Wilmarth, Phillip A; Chang, Min-lee et al. (2014) Newborn mouse lens proteome and its alteration by lysine 6 mutant ubiquitin. J Proteome Res 13:1177-89
Chiu, Chung-Jung; Chang, Min-Lee; Zhang, Fang Fang et al. (2014) The relationship of major American dietary patterns to age-related macular degeneration. Am J Ophthalmol 158:118-127.e1
Chaffee, Blake R; Shang, Fu; Chang, Min-Lee et al. (2014) Nuclear removal during terminal lens fiber cell differentiation requires CDK1 activity: appropriating mitosis-related nuclear disassembly. Development 141:3388-98
Weikel, Karen A; Garber, Caren; Baburins, Alyssa et al. (2014) Nutritional modulation of cataract. Nutr Rev 72:30-47
Chang, Min-Lee; Chiu, Chung-Jung; Shang, Fu et al. (2014) High glucose activates ChREBP-mediated HIF-1? and VEGF expression in human RPE cells under normoxia. Adv Exp Med Biol 801:609-21
Rowan, Sheldon; Weikel, Karen; Chang, Min-Lee et al. (2014) Cfh genotype interacts with dietary glycemic index to modulate age-related macular degeneration-like features in mice. Invest Ophthalmol Vis Sci 55:492-501
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
Weikel, Karen A; Fitzgerald, Paul; Shang, Fu et al. (2012) Natural history of age-related retinal lesions that precede AMD in mice fed high or low glycemic index diets. Invest Ophthalmol Vis Sci 53:622-32
Uchiki, Tomoaki; Weikel, Karen A; Jiao, Wangwang et al. (2012) Glycation-altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age-related disease (in nondiabetics). Aging Cell 11:1-13
Shang, Fu; Taylor, Allen (2011) Ubiquitin-proteasome pathway and cellular responses to oxidative stress. Free Radic Biol Med 51:5-16

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