Center for Molecular Medicine Cologne

Thomas Clahsen - assoc. RG 05

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

Abstract

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.

Clinical and Medical Relevance

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.

Project Related Publications

  1. Notara M, Lentzsch A, Clahsen T, Behboudifard S, Braun G, Cursiefen C. (2019) Bevacizumab Induces Upregulation of Keratin 3 and VEGFA in Human Limbal Epithelial Cells in Vitro. J Clin Med; Vol 8(11): E1925.
  2. Matthaei M, Hribek A, Clahsen T, Bachmann B, Cursiefen C, Jun AS. (2019) Fuchs Endothelial Corneal Dystrophy: Clinical, Genetic, Pathophysiologic, and Therapeutic Aspects. Annu Rev Vis Sci.; Vol 5:151-175.
  3. Hos D, Matthaei M, Bock F, Maruyama K, Notara M, Clahsen T, Hou Y, Le VNH, Salabarria AC, Horstmann J, Bachmann BO, Cursiefen C. (2019) Immune reactions after modern lamellar (DALK, DSAEK, DMEK) versus conventional penetrating corneal transplantation. Prog Retin Eye Res. Nov; Vol 73:100768.
  4. Buttner, C., Clahsen, T., Regenfuss, B., Dreisow, M. L., Steiber, Z., Bock, F., Reis, A., and Cursiefen, C. Tyrosinase Is a Novel Endogenous Regulator of Developmental and Inflammatory Lymphangiogenesis. Am J Pathol (2019); Vol 189: 440-448
  5. Hou Y, Le VNH, Clahsen T, Schneider AC, Bock F, Cursiefen C. (2017). Photodynamic Therapy Leads to Time-Dependent Regression of Pathologic Corneal (Lymph) Angiogenesis and Promotes High-Risk Corneal Allograft Survival. Invest Ophthalmol Vis Sci.; Vol 58(13): 5862-5869
  6. Regenfuß B, Dreisow ML, Hos D, Masli S, Bock F, Cursiefen C. (2015) The Naïve Murine Cornea as a Model System to Identify Novel Endogenous Regulators of Lymphangiogenesis: TRAIL and rtPA.
  7. Lymphat Res Biol.; Vol13(2): 76-84.
  8. Regenfuss B, Onderka J, Bock F, Hos D, Maruyama K, Cursiefen C. (2010) Genetic heterogeneity of lymphangiogenesis in different mouse strains. Am J Pathol.; Vol 177(1):501-10.
Dr. Thomas Clahsen CMMC Cologne
Dr. Thomas Clahsen

Clinic of General Ophthalmology

CMMC - assoc. Research Group

+49 221 478 32785

Clinic of General Ophthalmology

Department of Ophthalmology Kerpener-Str. 62

50937 Cologne

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Publications on PubMed

Publications - Thomas Clahsen

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