Identification of novel endogenous modulators of developmental and inflammatory lymphangiogenesis by analyzing mouse strain-specific differences

角膜是一个完善的模型来分析（淋巴）血管生成的机制。角膜作为模型的优点是其生理无血管性、透明度和暴露位置。在实验诱导的炎症之后，从角膜利姆布斯中预先存在的血管产生的血管和淋巴管都可以生长到角膜中。患者体内血管和淋巴管的向内生长不仅会导致视力下降，还会增加后续角膜移植后免疫反应的风险。我们的小组能够表明，无论是在发育上还是在炎症条件下，不同小鼠品系中角膜淋巴管生成反应的差异取决于遗传背景（C57 B16是“高”，BALBc是“低淋巴管生成”品系）。然而，个体间差异的潜在遗传原因只被部分理解。我们的假设-这些菌株依赖性差异允许识别淋巴管生成的新型内源性调节剂-已经在第一个资助期得到验证，例如TRAIL和酪氨酸酶被识别为淋巴管生成的新型内源性调节剂。第二阶段的重点在于进一步的候选基因，基因模块和途径，这是负责观察到的菌株依赖性差异，通过使用不同的近交系和协作杂交系和随后的功能分析的分子途径的新的淋巴管调节候选人的鉴定。本项目中发现的新型内源性调节因子可能有助于开发新的治疗靶点，用于治疗各种眼部和眼外疾病（如移植排斥或肿瘤转移）中的病理性淋巴管生成。

The cornea is a well-established model to analyze the mechanisms underlying (lymph)angiogenesis. Advantages of the cornea as a model are its physiological avascularity, transparency and exposed position. Following experimentally induced inflammation, both blood and lymphatic vessels arising from pre-existing vessels in the corneal limbus can grow into the cornea. The ingrowth of blood and lymph vessels in patients not only leads to reduced vision, but also increases the risk for immune reactions after subsequent corneal transplantation. Our group was able to show that both developmentally as well as under inflammatory conditions, differences in the lymphangiogenic response of the cornea in different mouse strains depend on the genetic background (with C57Bl6 being "high-" and BALBc being "low-lymphangiogenic" strains). However, the underlying genetic causes of the inter-individual differences are only partly understood. Our hypothesis - that these strain-dependent differences allow novel endogenous regulators of lymphangiogenesis to be identified - has already been validated in the first funding period with the identification of e.g. TRAIL and Tyrosinase as novel endogenous regulators of lymphangiogenesis. The focus of the second period lies in the identification of further candidate genes, gene modules and pathways, which are responsible for the observed strain-dependent differences by using different inbred strains and Collaborative Cross Lines and the subsequent functional analysis of molecular pathways of the novel lymphangioregulatory candidates. Novel endogenous regulators identified in this project may help to develop new therapeutic targets for the treatment of pathological lymphangiogenesis in a variety of ocular and extraocular diseases such as transplant rejection or tumor metastasis.