NEURO-VASCULAR INTERACTIONS IN THE DEVELOPING RETINA: EXPLORING THE CELLULAR ETHIOLOGY OF NORRIE DISEASE AND TESTING THE RATIONALE FOR EXPERIMENTAL THERAPEUTIC APPROACHES IN ANIMAL MODELS

Norrie Disease (ND) is a rare, hereditary disease. ND patients are blind, for the degeneration of the retina, the organ sensing light. Many patients suffer also hearing loss and mental retardation. To date there is no cure for ND. All ND patients have mutations in the NDP gene, as do patients with other eye diseases. Since the retina is always affected in NDP mutations, research is focused on this organ. In the milder cases defects in the NDP gene only damage the blood vessels of the retina. Thus, it has been suggested that in the most severe cases, such as ND, the blood vessels are so damaged that they do not provide enough oxygen to the retina, which degenerates. If proven true this hypothesis would support therapeutic expectations, since oxygen can be supplied from the outside. In the first part of the project we intend to test this issue, studying the retina of the mouse model for ND. The second part of the project is a study of how retinal neurons control the growth of blood vessels, a process of which the NDP gene is likely to be part, since it is expressed almost exclusively in the nervous system, and there its defects affect the formation of blood vessels. The development of retinal blood vessels proceeds by “growth on demand”. When oxygen levels become low, molecules are produced that make vessel grow, which bring in more oxygen. We know much of these molecules, very little of how neurons control this process. Neurons use much oxygen to fuel the machinery that allows them to communicate with one another, as they do since fetal life. Whether and how retinal embryonic activity regulates oxygen demand, and thus vessel growth, has not been studied. We intend to do so in this project. The relevance of this project may go beyond ND and the diseases associated to NDP mutations, extending to neurodegenerations related to blood vessel abnormal growth, such as retinopathy in diabetes and macular degeneration in the elderly.