Periodic Reporting for period 4 - GlymphEye (The Ocular Glymphatic System)
Période du rapport: 2022-03-01 au 2022-08-31
The publications defined that the eye, similar to the brain, has a highly polarized fluid transport system that exports amyloid-beta. Amyloid-beta has been implicated in Alzheimer diseases and in the eye in loss of retinal ganglion cells in glaucoma. The concept of a fluid transport system in the optic nerve is novel and important because it creates a framework that enable studies of disturbed fluid transport as a disease mechanism. The textbook concept is that the optic nerve only allows electrical signals to pass from the eye to the brain. We have shown that the optic nerves also transport fluid and metabolic waste products from the eye to the brain. Diseases of the eye, including glaucoma and macular degeneration, are very common and affects the life of a large proportion of the world’s population. Our mechanistic understanding of these diseases is still limited. Thus, there is no cure, and a limited number of treatments exists. Age-related ocular diseases, including glaucoma and macular degeneration involve abnormal accumulation of neuronal metabolic waste products. The overall objective of the project is to describe the ocular glymphatic system. We have not encountered problems in the studies and have been moving ahead as outlined in the proposal. Our most important publication published in 2020 defined the existence of the ocular glymphatic system. The publication has received considerable interest. This development is important for the society because it creates insight into new strategies for development of therapeutic of glaucoma and macular degeneration. We have concluded the experiments and we are in the midst of writing the final publications.
The proposed studies have all been completed. We have developed and refined the methodology to study the ocular glymphatic system. The basic methodology involves intravitreal injection of fluorescent tracers and harvest of the eye and optic nerve 30-120 min later. Several optical techniques have been used to analyze tracer transport. Additional studies have defined the basic properties of the ocular glymphatic system including the dependence on the molecular size and properties of the tracers. We have also defined the importance of intraocular or intracranial pressure and the effect of 2 independent models of glaucoma on ocular glymphatic transport. We demonstrated that fluid flow along the optic nerve could be defined as glymphatic flow, since fluid transport was highly polarized. Inflow of fluid occurs along the arteries, whereas efflux is along retinal ganglion cells axons and veins. Also, fluid flow along the optic nerve was facilitated by expression of the water channel aquaporin-4 and reduced in mice lacking aquaporin-4 channels. The main results have been published and additional studies are at the stage of manuscript writing.
We have developed and validated PET imaging studies of the ocular glymphatic system, which was not included in the original proposal. We have also expanded the number of diseases studied to include diabetic retinopathy.