Summary:The Inana laboratory uses molecular, cellular, genetic, and physiologic approaches to uncover the genes that cause retinal degeneration, including macular degeneration, to elucidate the mechanism by which defects in these genes lead to retinal/macular degeneration, and to develop the best treatment or cure for these diseases.

George Inana, M.D., Ph.D.
Professor of Ophthalmology
Director of Laboratory of Molecular Genetics

View published research articles by this doctor in the National Library of Medicine.

Current Research Summary

A number of projects are in progress in my laboratory, one major one being the discovery of new retinal degeneration genes. Several years ago, a novel subtractive cloning strategy developed in my laboratory was used to isolate new genes that are preferentially expressed in the human retina. Our hypothesis was that such genes should play important functional roles in the retina and if perturbed, should be good candidates to cause retinal disease. To date, five new retinal genes have been uncovered by this strategy, and consistent with our hypothesis, at least three of them have turned out to be related to retinal degeneration.

One of them, HRG4, is a novel photoreceptor synaptic protein, which was found to be mutated in a patient with late-onset cone-rod dystrophy. We have constructed an experimental model (transgenic, TG) of this disease that expresses the identical mutation, and have succeeded in demonstrating the presence of a late-onset retinal degeneration, just as in the human patient, in this model. The TG model develops ERG defects and severe synaptic degeneration accompanied by specific changes in retinal synaptic proteins. A mechanism involving mitochondrial stress and apoptosis has been shown to cause the synaptic degeneration in the TG model.  A knock-out model (KO) of HRG4 has also been constructed and shown to develop retinal degeneration with a phenotype quite different from that of the TG. Significantly, the KO model has revealed a new function of HRG4 which is in the distal end of photoreceptors related to protein transport from the inner segment to the outer segment. Elucidation of the function of HRG4 is progressing, including the identification of its target protein, ARL2, using the yeast two-hybrid strategy and testing of its postulated function through biochemical studies. Experimental evidence so far suggests that HRG4 may play a role in vesicle/membrane trafficking.

Another new retinal gene we have uncovered, X-arrestin localized on the X chromosome, is a cone photoreceptor-specific arrestin that has shown a mutation in a family with X-linked retinopathy. Arrestins have been shown to desensitize activated G-protein-coupled receptors such as rhodopsin and b-adrenergic receptor. Because of its unique pan-cone-specific pattern of expression, we have been molecularly dissecting the X-arrestin gene promoter to elucidate the mechanism of cone-specific expression, which may be therapeutically useful. Using mutagenesis of specific promoter elements and testing of different promoter constructs by transgenic expression, we have been able to close in on the specific promoter elements that may be responsible for the unique cone-specific expression of this gene. Another new gene  we have uncovered, HRG5, has turned out to be the regulator of  G protein signaling 9 (RGS9). RGS9 has been shown to be the GTPase accelerator for transducin, and therefore to play a role in the turning off of the phototransduction cascade. This gene is being screened for mutations in patients with retinal diseases, and preliminary results have shown an interesting pattern of polymorphisms that may be related to disease. Recently, a connection of this gene to ocular disease called bradyopsia was demonstrated, confirming our preliminary results.

Genes that may play a role in age-related macular degeneration are being pursued through novel strategies that identify disease-related genes. A custom gene expression profiling strategy called CHANGE, developed and in use in our laboratory for over ten years, is being used to identify genes that are important for both the mechanism of rod outer segment (ROS) phagocytosis by retinal pigment epithelium (RPE) and age-related macular degeneration (AMD). Phagocytosis of ROS by the RPE is a key daily function of the RPE cell, and disturbance of this process leads to accumulation of debris and retinal degeneration. Since a defect in this process is likely to result in accumulation of deposits in the RPE and Bruchs membrane which are pathologic changes seen in AMD, genes that show evidence of involvement in both the RPE phagocytosis of ROS and AMD are being sought. A number of candidate genes have been identified and are being analyzed. A candidate gene has been shown to be increased in AMD and also to play a role in ROS phagocytosis. A transgenic model that over-expresses this gene conditionally has been shown to develop a phenotype resembling dry and wet AMD, making this gene a possible therapeutic lead for AMD.