The primary goal of this research program is to begin to identify and characterize genes associated with the primate fovea and to elucidate the molecular manifestations of age-related macular degeneration (AMD). AMD is the most common cause of legal blindness in persons over 60 years of age in developed countries, affecting approximately 10% of the geriatric population. Pathological changes associated with AMD are most prevalent in the retinal macula and in the choroid and retinal pigment epithelium overlying this region. At the center of the macula there is a specialized, avascular region - the fovea - that contains the highest density of cone photoreceptor cells in the retina. These foveal cones are morphologically distinct from extrafoveal cones, are crucial for fine visual acuity and seem to be more susceptible to.degeneration in certain human diseases, including AMD. The bases for this predilection to disease are not understood, and little is known about the genes that contribute to the foveal cones' specialized structure and function. As such, the initial focus of this application will be to identify and characterize primate foveal cone-specific and -associated cDNAs. Transcripts unique to foveal cones will be identified by comparing them to transcripts derived from the peripheral retina, using mRNA differential display. Fovea-specific amplicons identified in this manner will be used as probes to isolate corresponding full-length cDNAs from fovea-enriched cDNA libraries. The molecular characteristics and distribution of the human foveal cDNA clones will be determined by DNA sequence analyses, in situ hybridization, chromosomal mapping and immunocytochemistry. Once characterized, the foveal clones will be used as molecular tools to help define age-related versus disease-related changes in normal human retinas and retinas obtained from eyes of donors afflicted with AMD. Additional studies will be directed toward identifying human retina-specific cDNAs that are differentially expressed as a consequence of AMD. Transcripts that are expressed specifically in retinas from donors with a diagnosed history of AMD, as compared to age-matched retinas from unaffected donors, will be identified using mRNA differential display. RNA fragments specifically expressed in either group will be characterized using the same approach outlined for characterizing foveal clones. We anticipate that these studies will add to our overall understanding of the molecular structure of the fovea, especially the foveal cone photoreceptors, and provide additional insight into the etiology of age-related macular degeneration.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011286-04
Application #
2615279
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Project Start
1995-12-04
Project End
1999-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Iowa
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Baer, Claxton A; Rickman, Catherine Bowes; Srivastava, Sunil et al. (2008) Recurrent choroidal neovascularization after macular translocation surgery with 360-degree peripheral retinectomy. Retina 28:1221-7
Wistow, Graeme; Peterson, Katherine; Gao, James et al. (2008) NEIBank: genomics and bioinformatics resources for vision research. Mol Vis 14:1327-37
Yu, Ling; Kelly, Una; Ebright, Jessica N et al. (2007) Oxidative stress-induced expression and modulation of Phosphatase of Regenerating Liver-1 (PRL-1) in mammalian retina. Biochim Biophys Acta 1773:1473-82
Bowne, Sara J; Liu, Qin; Sullivan, Lori S et al. (2006) Why do mutations in the ubiquitously expressed housekeeping gene IMPDH1 cause retina-specific photoreceptor degeneration? Invest Ophthalmol Vis Sci 47:3754-65
Malek, Goldis; Mace, Brian; Saloupis, Peter et al. (2006) Initial observations of key features of age-related macular degeneration in APOE targeted replacement mice. Adv Exp Med Biol 572:109-17
Bowes Rickman, Catherine; Ebright, Jessica N; Zavodni, Zachary J et al. (2006) Defining the human macula transcriptome and candidate retinal disease genes using EyeSAGE. Invest Ophthalmol Vis Sci 47:2305-16

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