ИСТИНА

В проекте будут впервые охарактеризованы механизмы действия секретируемого цинка в отношении нейротропной активности и сигнальных каскадов, регулирующих выживаемость нейронов сетчатки при глаукоме, возрастной макулярной дегенерации (ВМД) и диабетической ретинопатии (ДР).

Retinal neurodegenerative diseases such as glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR) represent an important medical problem since they are widespread in the population and represent a major cause of incurable vision loss. They have different etiologies related to the anatomical features and protein composition of the retina, its unique metabolic activity, photosensitivity, immune privilege and other specific properties. Recently (RSF grant # 21-15-00123), we have revealed that a common factor accompanying neurodegenerative changes in glaucoma and AMD is an increase in mobile zinc secreted in the retina and accumulated in the aqueous humor (AH) as low-affinity complexes (the role of secreted zinc in DR will be investigated in the current project). Moreover, we have identified potential signaling targets of cytotoxic zinc, the most significant of which is PEDF, the main neurotropic factor of the retina. Here, we propose that the main trigger of neuronal death may be a mobile zinc-induced deficit in general neurotropic activity in the retina mediated by PEDF and a set of other signaling factors. The targeting of complexes of these proteins with zinc may be of therapeutic importance, especially in view of their extracellular localization and the possibility of affecting them by intravitreal injections. Based on preliminary structural and transcriptomic studies, we have selected a set of probable signaling targets of extracellular zinc in the retina, including neurotropic factors PEDF and BDNF, factors VGF and IGF1, as well as signaling proteins WIF1, MYOC, and AGT, which regulate retinal neuronal survival and mechanisms of neurodegeneration. In addition, a number of new factors identified through exploratory experiments will be considered. According to our data, nonspecific chelation of zinc in vivo had no therapeutic effect due to the complex effect on biochemical processes in the retina. Therefore, a general neuroprotective approach may be the identification of key zinc-dependent signaling factors in each disease and the development of compensatory therapy using their genetically modified variants with altered zinc sensitivity. To solve this problem, we aimed at recognizing zinc-sensitive secreted neurotropic/signaling factors associated with glaucoma, AMD and/or DR at the patient level, as well as in animal and cellular models. We will determine the effects of zinc on their structure and interaction with cell surface receptors and other signaling proteins, identify (including resolving of crystal structures) zinc-binding sites, create their modified variants with specified zinc-binding properties and test the latter on retinal cell models and animal models of glaucoma and AMD. As a result, we will be able, firstly, to determine the impacts of secreted zinc on neurotropic activity in the retina and, secondly, to propose a new approach to prevent its aberrant signaling, which can be considered as a prospective therapy for retinal degenerative diseases and other neurodegenerative pathologies. In addition, we aimed at developing a new concept for early non-invasive diagnosis of retinal diseases based on our patented method of analyzing thermodynamic signatures of tear fluid (TF) with automatic classification using machine learning algorithms. A new high-throughput method of signature registration will be tested, which can facilitate the introduction of the diagnostic approach in clinical practice. Considering the simplicity of TF collection and analysis, the approach has potential as primary screening for a wide range of ophthalmologic diseases.