Age-related macular degeneration (AMD) is the leading cause of irreversible central visual loss in the aged population in the world. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation causes a predisposition to the disease. In 2003, we initiated this project by recruiting advanced AMD patients and age-control individuals with normal retinas. Up to date, 433 individuals have been enrolled and 60 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 FY2010, (1) We created material transfer agreements with 5 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 manuscript has been submitted for publication;(3) We continued characterizing ccl2/cx3cr1 deficient mice, a murine model of AMD. We found enhancing expression of PPAR, tissue factor, and HtrA2 on the retinal lesions of these mice. We reported the effect of Quercetin on the retinal lesions of ccl2/cx3cr1 deficient mice;(4) We continued testing various agents for therapeutic purposes in ccl2/cx3cr1 deficiency mice. We published the effect of Quercetin on cultured RPE cells and the retinal lesions of ccl2/cx3cr1 deficient mice. We also examined the suppressive effect of naloxone on the lesions in ccl2/cx3cr1 deficient mice by targeting microglia. We evaluated AAV-sFLT01 gene therapy on the ccl2/cx3cr1 deficient mice and reported at the 2010 ARVO meeting. In a collaboration with Dr. Prockop, we begun testing the effect of mesenchymal stem cell and its product on the retinal lesion of ccl2/cx3cr1 deficient mice;(4) We initiated a pharmacogenomic study on the relationship between the efficacy of Lucentis therapy on AMD and patients genotypes;(5) Three invited review papers were published.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAEY000418-07
Application #
8149169
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2010
Total Cost
$1,298,601
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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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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