Clahsen, Thomas - assoc. RG 05

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.

We were 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 C57BL/6 being “high-” and BALB/c being “low-lymphangiogenic” strains). However, the underlying genetic causes of the inter-individual differences are only partly understood. The use of these strain-dependent differences enables the identification of new endogenous regulators of lymphangiogenesis, as we have already demonstrated by the identification of both TRAIL and tyrosinase that have been confirmed as novel endogenous regulators of lymphangiogenesis.

Our focus 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 CollaborativeCross 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.

The cornea’s transparency is essential for vision. Different eye diseases, including infections lead to an ingrowth of blood and lymphatic vessels which results in loss of transparency. To date there are no available treatments in the clinic to specifically modulate lymphangiogenesis.
Identification of novel modulators of lymphangiogenesis and understanding of the involved pathway help to develop new therapeutic targets for the treatment of pathological lymphangiogenesis in a variety of ocular diseases such as tumor metastasis.