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.
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