We identify and topographically localize inflammatory, degenerative, and malignant cells, as well as their products in patient specimens and animal tissues. We analyze the cells and their products mainly by routine pathology, immunohistochemistry, and molecular pathology. The application of cutting-edge technology, such as microdissection combined with molecular techniques including PCR, RT-PCR, RQ-PCR and genotyping, allows us to provide more accurate pathological diagnosis (assessment) and pathogenesis of the disease. It also guides us in selecting the most appropriate treatment for patients. We learn a great deal about the mechanisms of different ocular diseases from various animal models. Using animal models, we can also access the efficacy of different therapeutic agents for various ocular diseases. This helps us better understand disease mechanisms and select specific therapies targeting particular diseases for our patients. In FY2010, we accomplished the following in our research: 1. Molecular Pathology of Age-Related Macular Degeneration (AMD): AMD is the leading cause of vision loss among the elderly in the United States, and the number of individuals affected is expected to increase 50% by the year 2020. The pathology of AMD is characterized with the accumulation of drusen, RPE degeneration, photoreceptor atrophy, and sometimes with choroidal neovascularization (CNV). While several risk factors, including age, race, smoking, and diet have been linked to AMD, the etiology and pathogenesis of the disease remain largely unclear. Treatment options for the condition are similarly limited. Recently, reports have shown that AMD development is strongly influenced by genetic factors. We and other investigators have reported significant associations between AMD and single nucleotide polymorphisms in CFH, CX3CR1, and ARMS2/HtrA1 over the past few years. Growing evidence also suggests that inflammatory and immunological elements (e.g., macrophages and microglia), apoptosis, cholesterol trafficking, angiogenesis (e.g., VEGF expression), and oxidative stress (e.g., the role of mitochondria) play an important role in AMD development. In FY2010, we studied peroxisome proliferator-activated receptor (PPAR) and tissue factor (TF) expression in a murine model (Ccl2/Cx3cr1 double deficient mice) and human eyes with AMD. We found and reported enhanced expression of PPAR and TF in the AMD lesions. We demonstrated the inhibitory effects of quercetin in cultured human RPE cells under oxidative stress, but not in Ccl2/Cx3cr1 double deficient mice. In addition, we published a comprehensive review on retinal ultrastructures of major murine dry AMD models. The aforementioned dry AMD murine models fall into three categories: genetically engineered mice, immunologically manipulated mice, and naturally occurring mouse strains. Most murine models are genetically engineered to manipulate genes that cause macular degeneration-like lesions in the retina. A detailed understanding of the differences between mouse and human biology will help guide and improve the efficacy of future research therapeutic trials. 2. Ocular Lymphoma: We have studied and reported systemic metastatic retinal lymphoma. Although they are extremely rare, they originate from both T- and B-cell lymphomas and have very high mortality. We used a 25-gauge transconjuctival sutureless vitrectomy for the diagnosis of intraocular lymphoma. We also presented two unusual primary retinal lymphoma cases, one with rapid progression and vision loss and the other following ocular toxoplasmosis;and a case of orbital lymphoma masquerading as panuveitis. We predict the future of primary retinal lymphoma holds an opportunity to really understand the unique cytological, histopathological, physiological and immunological features of the disease. Furthermore, there is a prospect of understanding the genotypic (gene expression, interaction, polymorphism, epigenetics, etc.) and epidemiologic traits of primary retinal lymphoma. This information will empower us to truly make a difference in patient management with this devastating disease. While most of this technology already exists, much work still needs to be done to make translational therapy a reality for the patients with ocular lymphoma in the future. 3. New Pathology and Pathogenesis of Ocular Diseases: We reported novel pathological findings for corneal disease in KID syndrome (keratitis, ichthyosis and deafness) and macular foveoschisis associated with degenerative myopia. The new findings provide insight on these rare diseases. We also presented rapid vision loss associated with fludarabine toxicity in three patients. The toxicity is related to significant loss of retinal bipolar and ganglion cells, as well as optic nerve atrophy on pathological examination. 4. Experimental Models for Various Ocular Diseases: In collaboration with Drs. Caspi, Gery, and Nussenblatt of the NEI, and Dr. Iadarola of the NIDCR, different models and mechanisms of ocular inflammation and corneal analgesics have been evaluated and published. The data is further described in the annual reports of these investigators.