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).
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