Abstract

The broad objective of this proposal is to identify a disease gene responsible for North Carolina macular dystrophy and to elucidate the underlying molecular mechanisms that lead to macular degeneration. North Carolina macular dystrophy (OMIM #136550) is an autosomal dominant, highly penetrant macular degeneration characterized by variable phenotypes including confluent drusen in the macula, macular atrophy, and choroidal neovascularization.
Three specific aims are designed to test the underlying central hypothesis: that the protein product of the gene for North Carolina macular dystrophy, designated as MCDR1, is essential for the normal function of the macula and that the macular degeneration phenotype is associated with mutations in the MCDR1 gene. The three specific aims are: 1) to identify the disease gene for North Carolina Macular Dystrophy, MCDR1; 2) to characterize the mRNA and protein expression profiles and function of MCDR1; 3) to study the biological effect of MCDR1 in a mouse system. It is important to study the genetic basis of North Carolina macular dystrophy, as it causes juvenile macular degeneration with visual loss. Furthermore, North Carolina macular dystrophy shares important clinical features with age-related macular degeneration (AMD). Drusen is a hallmark of AMD and choroidal neovascularization (CNV) is one of the most important complications of AMD. Both of them are present in patients with North Carolina macular dystrophy. Therefore, these observations make North Carolina macular dystrophy a unique genetic model for AMD. Understanding the molecular mechanisms of MCDR1 should lead to novel insights into the pathogenesis of macular degeneration. Elucidation of the function of the MCDR1 gene may increase our understanding of retinal cell biology in general and drusen formation in particular. Finally, this study may provide information for pursuing novel strategies for treatment of macular degeneration.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014448-05
Application #
7261200
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Chin, Hemin R
Project Start
2003-09-01
Project End
2008-07-19
Budget Start
2007-07-01
Budget End
2008-07-19
Support Year
5
Fiscal Year
2007
Total Cost
$561,849
Indirect Cost

  Institution

Name
University of Utah
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

Skowronska-Krawczyk, Dorota; Zhao, Ling; Zhu, Jie et al. (2015) P16INK4a Upregulation Mediated by SIX6 Defines Retinal Ganglion Cell Pathogenesis in Glaucoma. Mol Cell 59:931-40
Loomis, Stephanie J; Kang, Jae H; Weinreb, Robert N et al. (2014) Association of CAV1/CAV2 genomic variants with primary open-angle glaucoma overall and by gender and pattern of visual field loss. Ophthalmology 121:508-16
Bailey, Jessica N Cooke; Yaspan, Brian L; Pasquale, Louis R et al. (2014) Hypothesis-independent pathway analysis implicates GABA and acetyl-CoA metabolism in primary open-angle glaucoma and normal-pressure glaucoma. Hum Genet 133:1319-30
Wiggs, Janey L; Hauser, Michael A; Abdrabou, Wael et al. (2013) The NEIGHBOR consortium primary open-angle glaucoma genome-wide association study: rationale, study design, and clinical variables. J Glaucoma 22:517-25
Takeuchi, Tomokazu; Hayashi, Takaaki; Bedell, Matthew et al. (2010) A novel haplotype with the R345W mutation in the EFEMP1 gene associated with autosomal dominant drusen in a Japanese family. Invest Ophthalmol Vis Sci 51:1643-50
Chen, Haoyu; Zhang, Mingzhi; Tang, Shibo et al. (2010) Slit-Robo signaling in ocular angiogenesis. Adv Exp Med Biol 664:457-63
Khurana, Rahul N; Sun, Xufang; Pearson, Eric et al. (2009) A reappraisal of the clinical spectrum of North Carolina macular dystrophy. Ophthalmology 116:1976-83
Li, Feng; Marchette, Lea D; Brush, Richard S et al. (2009) DHA does not protect ELOVL4 transgenic mice from retinal degeneration. Mol Vis 15:1185-93
Yamashita, Tetsuji; Liu, Jiewu; Gao, Jiangang et al. (2009) Essential and synergistic roles of RP1 and RP1L1 in rod photoreceptor axoneme and retinitis pigmentosa. J Neurosci 29:9748-60
Yang, Zhenglin; Stratton, Charity; Francis, Peter J et al. (2008) Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N Engl J Med 359:1456-63

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