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. To date, 477 individuals have been enrolled and 115 histopathological cases with AMD and age-matched controls have been collected. We continue to analyze parts of 835 DNA samples from the Blue Mountain Eye Study from Australia and 534 DNA samples from the AREDS project in the USA, as some DNA samples have run 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 a useful tool for evaluating potential therapies for AMD. In FY2015, (1) we have continued to work with collaborators to use our DKO rd8 model to study disease pathogenesis and therapeutic approaches to AMD by evaluating the roles of gut commensal microbiota and Ixolaris, a tissue factor inhibitor (collaboration with Drs. Jose Ribero and Ivo Francischetti of NIAID) that were reported at ARVO 2015; (2) we published the association study between RAD51, FPR1 (collaboration with Dr. Calvin Pang of Chinese University of Hong Kong), and UBE3D (collaboration with Dr. Xiaoxin Li of Peking University) and AMD; (3) we performed in vitro studies on inflammasomes and related molecules/pathways with ARPE-19 cells, human RPE cells (collaboration with Dr. Shusheng Wang of Tulane Univeristy), and mouse retinal stem cells (collaboration with Ting Xie of Stowers Institute for Medical Research); (4) we evaluated cell death forms/pathways in RPE and photoreceptors that are the most critical cells in AMD. As of May 2015, the Immunopathology Section has closed with the retirement of the principal investigator, Dr. Chan.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000418-12
Application #
9155570
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2015
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
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
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

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