Functional relevance and molecular mechanisms of tyrosinase in controlling lymphangiogenesis in different ocular diseases

• Applicants: Dr. Thomas Clahsen; Professor Dr. Claus Cursiefen
• Subject Area: Ophthalmology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 492026992

The eye conventionally has been thought of as being devoid of lymphatic vessels. In recent years, however, it became clear that lymphatic vessels can enter the eye under certain, usually inflammatory conditions (e.g. into the normally avascular cornea). These newly formed lymphatic vessels significantly increase the risk of graft rejections after subsequent corneal transplantation. Furthermore, it was shown that Schlemm’s canal, part of the ocular drainage pathway regulating intraocular pressure, displays features of an atypical lymphatic vessel and that experimental modulation of lymphangiogenesis can affect glaucoma development. Recently an intimate functional and anatomical relationship between (cutaneous) stem cells and lymphatic vessels was described. Whether such a role of limbal lymphatics exists for limbal stem cells is yet unknown.We recently identified the tyrosinase gene, a key enzyme in melanogenesis, as a novel endogenous modulator of both developmental and inflammatory lymphangiogenesis. Tyrosinase is primarily expressed in melanocytes in the skin but is also found in different compartments of the eye, such as the uvea, retinal pigment epithelium, and in the limbal area. Furthermore, tyrosinase is also significantly involved in the developmental process of the eye and has a putative function as modifier of the drainage structure phenotype in primary congenital glaucoma. The functional relevance of tyrosinase in regulating ocular lymphatic vessels at different locations is yet unclear, but pilot data from our group suggest tyrosinase to be critically involved in e.g. regulating corneal graft rejection.Based on these findings, we hypothesize that a better understanding of the functional relevance and the molecular mechanisms of ocular tyrosinase in the regulation of (pathological) ocular lymphangiogenesis will enable new ocular treatment approaches. Therefore, this project has three specific aims: (i) to analyze the functional relevance and underlying molecular mechanism of tyrosinase in regulating ocular lymphangiogenesis using different ocular disease models. Specifically, we will analyze the influence of tyrosinase on lymphatic vessels and lymphangiogenesis in the context of corneal transplantation and transplant immunology. (ii) to analyze the relevance of ocular tyrosinase in regulating intraocular pressure via influencing Schlemm’s canal. (iii) to identify a potential role of ocular tyrosinase in maintaining limbal stem cell niche homeostasis Our findings will provide novel therapeutic strategies to modulate (pathological) corneal lymphangiogenesis/lymphatic vessel function in corneal transplantation, glaucoma, and limbal stem cell disease.

• DFG Programme: Research Grants