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, 465 individuals have been enrolled and 107 histopathological cases with AMD have been collected. We continue to analyz 835 DNA samples from the Blue Mountain Eye Study in Australia and 534 DNA samples from the AREDS project in USA. 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 (DKO rd8) mice) was generated to act as an AMD model in 2007. In FY2012, (1) we signed 2 additional material transfer agreements with 2 other extramural research institutes and transferred living DKO rd8 mice to them for collaborative studies of mechanisms and therapeutic options;(2) we continued characterizing DKO rd8 mice, a paper of 3D optical coherence tomography assessment (collaboration with Dr. Nicholas Bazan) was published (Zhou, et al. Exp Eye Res 2011;93:636-648);(3) we evaluated the anti-inflammatory and suppressive effect of TSG-6 recombinant protein (collaboration with Dr. Prockop) on the retinal lesions and published a paper (Tuo, et al. Neuroinflammation 2012;9:59). Currently, we are evaluating other compounds such as PDGF-CC (collaboration with Dr. Xuri Li), PEDF (collaboration with Dr. Becerra) and STC-1 (continue collaboration with Dr. Prockop) by using this animal model;(4) we provided DKO rd8 retina to collaborators for studies on microarray (collaboration with Dr. Mengqing Xiang and microRNA involvements in AMD (collaboration with Dr. Shusheng Wang);(5) using paraffin-embeded, archived slides, we studied the role of macrophage polarization in AMD and published our results (Cao, et al. Pathol Int 2011;61:528-535);(6) we conducted a pharmacogenomic study (collaboration with Drs. Catherine Meyerle, Richard Rosen and Shree Kurup) on the efficacy of anti-VEGF therapy on AMD and patients genotypes and currently have the manuscript under review in Molecular Vision;(7) we performed a large scale SNP association study on the role of TIMP3 in AMD and have the manuscript under review in Eur J Hum Genet;(8) we published a review paper on the genetics of inflammation in AMD (Tuo, et al. Ocul Immunol Inflamm 2012;20:27-36) and a chapter regarding the role of oxidative stress in DKO rd8 mice (Tuo. Chapt 17 in Studies on Retinal and Choroidal Disorders (Stratton, Hauswirth, Gardner, eds.) Humana Press, 2012, pp. 355-365).

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000418-09
Application #
8556833
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2012
Total Cost
$1,000,820
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
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
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
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
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
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
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
Wang, Yujuan; Subramanian, Preeti; Shen, Defen et al. (2013) Pigment epithelium-derived factor reduces apoptosis and pro-inflammatory cytokine gene expression in a murine model of focal retinal degeneration. ASN Neuro 5:e00126

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