Age-related macular degeneration (AMD) causes irreversible central visual loss in the aged population. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation places 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, 449 individuals have been enrolled and 107 histopathological cases with AMD have been collected. We continue analyzing 835 DNA samples from the Blue Mountain Eye Study in Australia and 534 DNA samples from a historical AREDS in USA. We are comparing the allelic frequencies of single nucleotide polymorphisms (SNPs) within candidate genes between AMD and control subjects followed by the 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 has been generated to act as the AMD model. In FY2011, (1) We created material transfer agreements with 3 additional extramural research institutes and sent them living mice (ccl2/cx3cr1 deficiency) to study mechanism and therapeutic options for AMD;(2) Using previous established platforms, we completed the study on copy number variation of 8 genes and AMD association. The result has been published in IOVS;(3) We continued characterizing ccl2/cx3cr1 deficient mice, a murine model of AMD, in ultrastructure. We found pathological changes in synapse and tissue factor expression on the retinal lesions of these mice. We reported the synapse data in ARVO 2011 and published the result of tissue factor in full article;(4) We evaluated the suppressive effect of naloxone on the lesions by targeting microglia and evaluated AAV-sFLT01 gene therapy in the ccl2/cx3cr1 deficient mice and published the results in two articles (Shen, IOVS and Tuo, Neurobiol Aging). Currently, we are testing the effects of other compounds such as PDGF-CC and PEDF by using this animal model. In a collaboration with Dr. Prockop, we tested the effect of TSG-6, a secreted protein from the mesenchymal stem cells on the retinal lesion of ccl2/cx3cr1 deficient mice and reported in ARVO 2011;(5) We conducted a pharmacogenomic study on the relationship between the efficacy of anti-VEGF therapy on AMD and patients genotypes and results were presented in ARVO 2011;(6) We provided the genomic material to collaborators for studies on epigenetic and immunological involvements in AMD, and verification of Genome-Wide Association Study; (7) Three invited review papers were published and two book chapters were prepared.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000418-08
Application #
8339775
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2011
Total Cost
$1,048,901
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
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
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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
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

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