Skip to Main Content

George Inana, M.D., Ph.D.

George Inana, M.D., Ph.D.

George Inana, M.D., Ph.D.

Research Subject

Genetics of Retinal Disease

Focus

Visual Processes, Retinal Degeneration, Macular Degeneration

Published Articles


Roles

Professor of Ophthalmology and Director of Laboratory of Molecular Genetics

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.


Current Research

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/UNC119, is a novel photoreceptor 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/UNC119 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/UNC119 which is in the distal end of photoreceptors. Recently, we demonstrated that HRG4/UNC119 mediates the transport of the phototransduction protein, transducin alpha, from the inner to the outer segment of photoreceptors by binding to the acyl group of the protein. This work was recently published and featured in News and Views in the journal Nature Neuroscience. Elucidation of the function of HRG4/UNC119 is continuing, including the identification of its target protein, ARL2, using the yeast two-hybrid strategy and testing of its postulated function through biochemical studies.

Other new retinal genes we have uncovered include X-arrestin localized on the X chromosome, which is a cone photoreceptor-specific arrestin that has shown a mutation in a family with X-linked retinopathy. 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). Preliminary results of screening have shown an interesting pattern of polymorphisms in this gene that may be related to disease. Recently, a connection of this gene to an 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. Among them, a candidate gene, MT1-MMP, 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. A therapeutic test comparing anti-MT1-MMP and anti-VEGF antibodies in our transgenic model and also the mouse laser photocoagulation model of choroidal neovascularization (CNV), a hallmark of wet AMD, demonstrated that anti-MT1-MMP treatment is superior in suppressing the CNV. Also, since cigarette smoking is a firmly established environmental factor for AMD, we have been identifying genes that are affected by smoking through gene expression profiling and comparing them to the AMD candidates that were identified by CHANGE. Again, several genes have shown an overlap, and their causal relationships to AMD are being investigated.