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, 476 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. While caution must always be taken in translating findings in mouse models to findings in humans, the AMD-like phenotype of DKO rd8 makes the model an useful tool for evaluating potential therapies for AMD. In FY2014, (1) 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 PEDF (collaboration with Dr. S. Patricia Becerra), anti-LRP6 antibody in wnt singaling pathway(collaboration with Drs. Jinxing Ma and Heping Xu);(2) we provided DKO rd8 retina for studying the microRNAs role in AMD (collaboration with Drs. Shusheng Wang and Mengqing Xiang);(3) we published the association study between RBD51B and AMD in our cohorts;(4) a large scale SNP association study on the role of FBN2 in AMD was published. A similar study on the role of SNPs in 3-UTR regions of various genes in AMD is ongoing;(4) 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;(5) we performed in vitro studies with ARPE-19 cells, human fetal RPE cells (collaboration with Dr. Sheldon Miller), and mouse retinal stem cells (collaboration with Ting Xie);(6) In this period, we published a total of 14 original or review papers including the novel findings of FBN2 gene in AMD.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000418-11
Application #
8938317
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
U.S. National Eye Institute
Department
Type
DUNS #
City
State
Country
Zip Code
Huang, Lv-Zhen; Li, Ying-Jie; Xie, Xue-Feng et al. (2015) Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations. Nat Commun 6:6687
Knickelbein, Jared E; Chan, Chi-Chao; Sen, H Nida et al. (2015) Inflammatory Mechanisms of Age-related Macular Degeneration. Int Ophthalmol Clin 55:63-78
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
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
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
Liang, X Y; Chen, L J; Ng, T K et al. (2014) FPR1 interacts with CFH, HTRA1 and smoking in exudative age-related macular degeneration and polypoidal choroidal vasculopathy. Eye (Lond) 28:1502-10
Ogilvy, Alexander J; Shen, Defen; Wang, Yujuan et al. (2014) Implications of DNA leakage in eyes of mutant mice. Ultrastruct Pathol 38:335-43
Ardeljan, Christopher P; Ardeljan, Daniel; Abu-Asab, Mones et al. (2014) Inflammation and Cell Death in Age-Related Macular Degeneration: An Immunopathological and Ultrastructural Model. J Clin Med 3:1542-60
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
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

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