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

传统上认为眼睛没有淋巴管。然而，近年来，很明显，淋巴管可以在某些通常是炎症的情况下进入眼睛（例如进入正常无血管的角膜）。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，它表明，施累姆氏管，调节眼内压的眼引流途径的一部分，显示出一个非典型的淋巴管的功能和淋巴管生成的实验调制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密切功能和解剖关系。角膜缘干细胞是否存在这样的作用还不清楚，我们最近发现酪氨酸酶基因，黑素生成的关键酶，作为一种新的内源性调节剂的发展和炎症淋巴管生成。酪氨酸酶主要在皮肤中的黑素细胞中表达，但也在眼睛的不同隔室中发现，例如葡萄膜、视网膜色素上皮和角膜缘区域。此外，酪氨酸酶还显著参与眼睛的发育过程，并且具有作为原发性先天性青光眼中的引流结构表型的修饰剂的推定功能。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，但来自我们小组的初步数据表明酪氨酸酶在例如调节角膜移植物排斥中起关键作用。我们假设，更好地了解眼酪氨酸酶在调节视网膜神经元凋亡中的功能相关性和分子机制，（病理性）眼部淋巴管生成将使新的眼部治疗方法成为可能。因此，本研究有三个目的：（1）利用不同的眼部疾病模型，分析酪氨酸酶在调节眼部淋巴管生成中的功能相关性和潜在的分子机制。具体而言，我们将分析酪氨酸酶对淋巴管和淋巴管生成的影响，在角膜移植和移植免疫学的背景下。(ii)分析眼酪氨酸酶通过影响Schlemm管调节眼压的相关性。(iii)鉴定眼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发现将提供新的治疗策略来调节角膜移植、青光眼和角膜缘干细胞疾病中的（病理性）角膜淋巴管生成/淋巴管功能。

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.