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

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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.