Aims

Abstract

Gap junctions (GJ) have been found in the retina almost 40 years ago and their crucial role in signaling has repeatedly been proven. GJs have also been reported to serve a mechanism known as the bystander effect by which neurons in the degrading tissue spread apoptosis via the enigmatic ‘death-signal’ molecule to their neighbors. It has therefore been proposed that a GJ blockade could serve to rescue neurons in progressive retinal diseases such as diabetic retinopathy, ischemia or glaucoma. However, GJs also serve as conduits of neuronal signals between neurons thus their chronic blockade would result in a loss of visual function. Therefore, we propose that GJs could be utilized as tools that promote neuron survival by the intercellular passage of rescue molecules rather than the death signal. In this scheme, the delivery of rescue molecules (‘health-signals’ in this proposal) would be followed by the cell-to-cell spreading of the compound through retinal GJs. The hypothesis works only if ‘health-signal’ molecules bear with a size, charge and 3D structure that allows them to travel across GJs. In this study we utilize GJ coupled retinal cellular networks to test the feasibility of transjunctional diffusion of epigenetic factors (miRNA transcripts), second messengers of intercellular cascades (IP3, cAMP, cGMP, Ca++) and clinically active compounds (Dexamethasone). Such spreading has a great potential to enhance the effects of gene therapy of various neurological diseases.

Aims of the project

  • To characterize the physical and chemical barriers of molecules that limit GJ mediated diffusion of hypothetical health-signals.

  • To characterize endogenous signal molecules and/or epigenetic factors that could be used as heath-signals

  • To characterize medications that can pass GJs

  • To test the above molecules in animal models of retinal diseases, including RP

  • To find homologies in the progression of RP in retinas of human patients and animal models, thus revealing potential clinical relevance of the above findings

Keywords

Imaging techniques, Pharmacology, Electrophysiological approaches, inflammation, Animal studies, retina, gap junction, coupling, retinal degeneration, retinal pigment epithelium

Project team

Bela Volgyi (Coordinator)

Hungary (NKFIH)

Karin Dedek (Participant)

Germany (BMBF)

Stanislao Rizzo (Participant)

Italy (MOH)