Research objectives and content
Age related macular degeneration (ARMD), involving the progressive loss of central vision currently effects an estimated 5-10 million people within the European Community. Since there are no effective therapies for this condition, the financial burden on social and health care services throughout the community is highly significant. ARMD has a significant genetic component to its etiology. Studies on less common forms of retinal degeneration which segregate in families according to mendalian ratios readily yield etiologic genes which, in some instances, have been implicated in age related forms of retinal disease such as retinitis pigmentosa and age related macular degeneration. For example, genes encoding rds-peripherin, and a tissue inhibitor of metalloproteinases (TIMP3) have been implicated in mendalian forms of macular degeneration, and mutations within the rim glycoprotein gene, the protein product which constitutes a component of the outer segment discs of the photoreceptor cells, have been implicated in age related forms of macular disease. It may become possible to develop genetic methods of intervention in the prevention of such conditions. To this end, a thorough understanding of the genetic etiologies of this group of conditions is required, together with a range of animal models through which explorations on gene delivery to retinal tissues may be explored. At the host institute, research is being undertaken into the molecular genetics of a number of degenerative retinal diseases, including retinis pigmentosa, Stargardt macular dystrophy, congenital stationary blindness and age related macular degeneration . A number of genes involved in the etiologies of such conditions having been localised and/or isolated at the host institute. In addition, small animal models are being developed through which the efficiency of viral and non-viral mediated gene delivery systems can be systematically evaluated. One such model, a mouse carrying a targeted distruption of the rhodopsin gene (Rho) was reported earlier this year (Humphries, M.M. et al., 1997). As part of this ongoing programme of research we propose to cross transgenic strains of mice expressing Bc12 (an anti-apoptotic gene) in rod photoreceptors, onto Rho/c-fos-- mice. Evidence is now available from naturally occuring animal models of degenerative retinal disease that a common pathway of photoreceptor cell degeneration is via apoptotic mechanisms.
Training content (objective, benefit and expected impact)
The objectives of this research are to determine whether photoreceptor cell degeneration can be inhibited in Rho-- mice on an anti-apoptotic genetic background. If so future strategies for photoreceptor cell protection in Rho-- mice could incorporate the delivery not only of functional rhodopsin genes but also those encoding a
photoreceptor-specific Bc12 cellular proto oncogene and suppression effectors of the c-fos cellular proto oncogene. This project will involve experience in the generation of animal models, and will provide experience in methods of histopathological assessment, as well as molecular genetic analysis.