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

传统上，眼睛被认为没有淋巴管。然而，近年来，在某些通常是炎症的情况下，淋巴管可以进入眼睛(例如进入正常的无血管角膜)，这一点变得很清楚。这些新形成的淋巴管显著增加了后续角膜移植后移植物排斥反应的风险。此外，研究还表明，Schlemm管是调节眼压的眼内引流途径的一部分，具有非典型淋巴管的特征，淋巴管生成的实验调节可以影响青光眼的发展。最近描述了(皮肤)干细胞和淋巴管之间的一种密切的功能和解剖关系。角膜缘淋巴管对角膜缘干细胞是否存在这样的作用尚不清楚。我们最近发现酪氨酸酶基因是黑素合成的关键酶，是发育和炎症淋巴管生成的新的内源性调节因子。酪氨酸酶主要在皮肤的黑素细胞中表达，但也存在于眼睛的不同区域，如葡萄膜、视网膜色素上皮和角膜区。此外，酪氨酸酶还显著参与眼睛的发育过程，并被认为是原发性先天性青光眼引流结构表型的修饰者。酪氨酸酶在调节不同位置的眼淋巴管中的功能相关性尚不清楚，但我们小组的初步数据表明，酪氨酸酶在调节角膜移植排斥反应等方面起关键作用。基于这些发现，我们推测，更好地理解眼部酪氨酸酶在调节(病理性)眼淋巴管生成中的功能相关性和分子机制将使新的眼部治疗方法成为可能。因此，本项目有三个具体的目标：(1)利用不同的眼病模型，分析酪氨酸酶在调节眼淋巴管生成中的功能相关性和潜在的分子机制。具体地说，我们将在角膜移植和移植免疫学的背景下分析酪氨酸酶对淋巴管和淋巴管生成的影响。(2)分析眼内酪氨酸酶通过影响Schlemm管调节眼压的相关性。(Iii)为了确定眼部酪氨酸酶在维持角膜缘干细胞生态位稳态中的潜在作用，我们的研究结果将为调节角膜移植、青光眼和角膜缘干细胞疾病的(病理性)角膜淋巴管生成/淋巴管功能提供新的治疗策略。

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.