rd1 Photoreceptor Degeneration: Photoreceptor Rescue and Role of Metalloproteases in Retinal Degeneration

Abstract: The thesis is focused on an attempt to delay photoreceptor cell death in the rd1 mouse using Lens Epithelium Derived Growth Factor (LEDGF), Glutathione S-Transferase mu (GST-?? and Glutathione S-Transferase alpha (GST-?? in an organ culture paradigm as well as the role of metalloproteases (MMPs) and their tissue inhibitors in photoreceptor degeneration (TIMPs).

The rd1 mouse model displays a retina degeneration which starts around day 10 with rod photoreceptor cell death. By 21 days after birth virtually all rod photoreceptors in the retina have died, and subsequent cone degeneration starts. The latter process is somewhat slower and by the age of 3-4 months, the animal has practically no photoreceptors left. In order to study the effect of factors which delay or halt the photoreceptor degeneration, a long term retina organ culture has been used. The culture medium of this culture paradigm was devoid of fetal calf serum (FCS) as FCS by itself contains an unknown number of growth factors which can synergistically interact on the rescue mechanisms together with the tested substance. In order to provide a chemically defined environment for the test paradigm, the culture medium was further developed to function without the addition of any FCS. Using this improved culture paradigm, a moderate but clear photoreceptor rescue was demonstrated using LEDGF. Also GSTs were tested and found to exhibit a rescue effect on photoreceptor degeneration. The mechanism(s) of photoreceptor cell death (apoptosis) in the rd1 mouse is not completely understood and is probably not involving the established caspase dependent apoptotic pathways. MMPs and TIMPs are involved in apoptotic processes. To enlighten their role in photoreceptor cell death, a study on the normal presence of these substances in the wild type retina and their changes in the rd1 mouse was performed.