The overall goal of this laboratory is to determine the molecular factors involved in macular degeneration, a leading cause of blindness in the US. We are taking a three-pronged approach to investigating macular degeneration 1) isolation and characterization of genes differentially expressed in macular over peripheral retina 2) isolation of genes at known macular degeneration loci and 3) mutational analysis of patients with age-related macular degeneration. In the first approach we used a solid-phase subtraction technique to clone a number of macula specific and macula enriched genes that are giving promising insights into the different biochemical pathways that are most important to the macula. Some of these genes are possible candidates for hereditary macular disease. We have constructed four cDNA libraries from neural macula, macular PE/choroid, peripheral neural retina and peripheral PE/choroid using fresh monkey retinal tisse. We are using these libraries to refine our search for differentially and/or uniquely expressed genes in those tissues. The second approach involves the systematic search for genes in a particular area of the genome. In collaboration with Dr. Kent Small at Jules Stein Eye Institute we are searching for the gene causing North Carolina macular dystrophy (MCDR1) in 6p14-q16.2. The gene is contained within two PAC clones and we are presently using these clones to screen our macula libraries. The third approach involves the mutational screening of approximately 1000 patients and age-matched controls suffering from age-related macular degeneration. This project will use patients from the NEI funded Age-Related Eye Disease Study (AREDS). This is a large multicenter research program designed to improve our understanding of the predisposing factors, clinical course, and prognostic factors of AMD and cataract. This information can then be used to determine the genetic risk factors for AMD and to initiate further study on the identified genes. Ultimately, it is hoped that this information will lead to treatments or preventive therapies for AMD. This study proposes to screen the AREDS patients to find mutations or sequence variants in a group of well-characterized genes known to be involved in a fundamental retinal function or to cause retinal disease. The purpose is to find sequence variants that statistically correlate with AMD. The finding of genetic defects associated with AMD will be important in understanding the pathophysiology as well as in developing new treatments or methods of prevention. Recent advances in technology facilitating high-volume genetic screening of patients provide a novel approach to investigating these diseases.
