Age-related macular degeneration (AMD) causes irreversible central visual loss in the aged population worldwide. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation creates a predisposition to the disease. In 2003, we initiated this project by recruiting advanced AMD patients and age-matched control individuals with normal retinas. Up to date, 482 individuals have been enrolled and 107 histopathological cases with AMD have been collected. We continue to analyze parts of 835 DNA samples from the Blue Mountain Eye Study in Australia and 534 DNA samples from the AREDS project in USA because some DNA samples had been ran out. We have compared the allelic frequencies of single nucleotide polymorphisms (SNPs) within candidate genes between AMD and control subjects, followed by functional studies of these SNPs by in vitro and/or in vivo experiments. Through this approach, we have identified genetic risk factors of AMD and the possible roles of these gene variations in the pathogenesis of the disease. Based on the information obtained from the above approaches, a genetically engineered animal (Ccl2/Cx3cr1 double deficiencies on rd8 background mice, DKO rd8) was generated to act as an AMD model in 2007. In FY2013, (1) we published the merits of using the DKO rd8 mouse model as a platform to screen therapeutic compounds for AMD treatment (Chu, et al. Bioengineered 5:13-15, 2013;Zhang, et al. Synapse 67:515-531, 2013;Wang, et al. Apoptosis 17:1144-1155, 2012);(2) we continue working with collaborators to use our DKO rd8 model to study disease pathogenesis and therapeutic options of AMD, by evaluating the roles of PDGF-CC (collaboration with Dr. Xuri Li), PEDF (collaboration with Dr. S. Patricia Becerra), TSG-6 (collaboration with Dr. Darwin Prockop: J Neuroinflamm e959, 2012) and AREDS II formula (Ramakumar, et al. J Nutr 143:1129-1135, 2013). The role of AREDS II formula has been published;(3) we initiated a study of antibody therapy to block WNT pathway in the retinal tissue of the DKO rd8 mice (collaboration with Dr. Wen-xin Ma);(4) we provided DKO rd8 retina for studying the microRNAs role in AMD (collaboration with Dr. Shusheng Wang);(5) we reported the pharmacogenomics study (collaboration with Drs. Catherine Meyerle, Richard Rosen and Shree Kurup) on the efficacy of anti-VEGF therapy on AMD and patients genotypes (Wang, et al. Mol Vis 18:2578-2585, 2012);(6) A large scale SNP association study on the role of TIMPs in AMD was published. A similar study on the role of DNA repair gene RAD51B in AMD is completed and the paper is in Eur Hum Genet (2013 Feb 20. doi: 10.1038/ejhg.2013.14);(7). some subjects recruited in this protocol were screened for their AMD related genotypes and will be used in the iPS project in collaboration with Drs. Sheldon Miller and Kapil Bharti;(8) we used a systems biology subtyping of AMD on the basis of gene expression (Abu-Asab, et al. J Ophthalmology 2013, in press) and reviewed how to distinguish AMD from aging (Ardeljan, Prog Retin Eye Res. 2013 Aug 9. doi:pii: S1350-9462(13)00045-1 Epub ahead of print);(9) in this period, we published a total of 13 relevant original or review papers including the novel findings of hypomethylation of the IL17RC promoter in AMD (collaboration with Dr. Lai Wei &Robert Nussenblatt: Cell Report 2:1151-1158, 2012) and the 7 new loci associated with AMD (collaboration with Dr. Anand Swaroop and the AMD Gene Consortium: Nat Genet 45:433-439, 2013).

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000418-10
Application #
8737634
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2013
Total Cost
$791,913
Indirect Cost
Name
U.S. National Eye Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Chu, Xi K; Meyerle, Catherine B; Liang, Xiaoling et al. (2014) In-depth analyses unveil the association and possible functional involvement of novel RAD51B polymorphisms in age-related macular degeneration. Age (Dordr) 36:9627
Promsote, Wanwisa; Veeranan-Karmegam, Rajalakshmi; Ananth, Sudha et al. (2014) L-2-oxothiazolidine-4-carboxylic acid attenuates oxidative stress and inflammation in retinal pigment epithelium. Mol Vis 20:73-88
Ardeljan, Daniel; Wang, Yujuan; Park, Stanley et al. (2014) Interleukin-17 retinotoxicity is prevented by gene transfer of a soluble interleukin-17 receptor acting as a cytokine blocker: implications for age-related macular degeneration. PLoS One 9:e95900
Ogilvy, Alexander J; Shen, Defen; Wang, Yujuan et al. (2014) Implications of DNA leakage in eyes of mutant mice. Ultrastruct Pathol 38:335-43
Chan, Chi-Chao; Ardeljan, Daniel (2014) Molecular pathology of macrophages and interleukin-17 in age-related macular degeneration. Adv Exp Med Biol 801:193-8
Tuo, Jingsheng; Shen, Defen; Yang, Howard Hua et al. (2014) Distinct microRNA-155 expression in the vitreous of patients with primary vitreoretinal lymphoma and uveitis. Am J Ophthalmol 157:728-34
Wang, Yujuan; Abu-Asab, Mones S; Yu, Cheng-Rong et al. (2014) Platelet-derived growth factor (PDGF)-C inhibits neuroretinal apoptosis in a murine model of focal retinal degeneration. Lab Invest 94:674-82
Ardeljan, Daniel; Chan, Chi-Chao (2013) Aging is not a disease: distinguishing age-related macular degeneration from aging. Prog Retin Eye Res 37:68-89
Ramkumar, Hema L; Tuo, Jingsheng; Shen, De F et al. (2013) Nutrient supplementation with n3 polyunsaturated fatty acids, lutein, and zeaxanthin decrease A2E accumulation and VEGF expression in the retinas of Ccl2/Cx3cr1-deficient mice on Crb1rd8 background. J Nutr 143:1129-35
Chu, Xi K; Wang, Yujuan; Ardeljan, Daniel et al. (2013) Controversial view of a genetically altered mouse model of focal retinal degeneration. Bioengineered 4:130-5

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