Project 2 Modulators of LA

Identification of novel endogenous modulators of (inflammatory) lymphangiogenesis by analyzing mouse strain-specific differences

Summary

The cornea is a well-established model to analyze the mechanisms of blood and lymphatic vessel growth (angiogenesis and lymphangiogenesis). Advantages of the cornea as a model are its physiological avascularity and transparency. Nonetheless, following inflammation experimentally as in patients, both blood and lymphatic vessels arising from pre-existing vessels in the corneal limbus can grow into the cornea. In patients this not only reduces vision but also increases the risk for immune reactions after subsequent corneal transplantation. Previous data from our group demonstrate that corneal lymphangiogenesis differs strain-dependently between mouse strains under inflammatory conditions and additionally in the limus of the healthy resting cornea. However, the underlying genetic causes of the inter-individual differences have not been studied in detail yet. Therefore, the focus of the project lies on the identification of candidate genes which are responsible for the observed strain dependent differences and on the analysis of molecular pathways of novel lymphangioregulatory candidates. Targeting of novel endogenous regulators could not only reduce immune reactions and promote graft survival after (corneal) transplantation but also could be used to treat tumors with lymphogenic metastasis and regulate inflammatory processes.

Publications

Cursiefen C, Bock F, Clahsen T, Regenfuss B, Reis A, Steven P, Heindl LM, Bosch JJ, Hos D, Eming S, Grajewski R, Heiligenhaus A, Fauser S, Austin J, Langmann T. [New Therapeutic Approaches in Inflammatory Diseases of the Eye – Targeting Lymphangiogenesis and Cellular Immunity: Research Unit FOR 2240 Presents Itself]. Klin Monbl Augenheilkd. 2017 May;234(5):679-685.

Regenfuß B, Dreisow ML, Hos D, Masli S, Bock F, Cursiefen C. The Naïve Murine Cornea as a Model System to Identify Novel Endogenous Regulators of Lymphangiogenesis: TRAIL and rtPA. Lymphat Res Biol. 2015;13(2):76-84.

Cursiefen C, Viaud E, Bock F, Geudelin B, Ferry A, Kadlecová P, Lévy M, Al Mahmood S, Colin S, Thorin E, Majo F, Frueh B, Wilhelm F, Meyer-Ter-Vehn T, Geerling G, Böhringer D, Reinhard T, Meller D, Pleyer U, Bachmann B, Seitz B. Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: The I-CAN study. Ophthalmology. 2014;121:1683-92.

Contreras-Ruiz L, Regenfuss B, Mir FA, Kearns J, Masli S (2013) Conjunctival inflammation in thrombospondin-1 deficient mouse model of Sjogren’s syndrome. PLoS One 8(9): e75937.

Bock F, Maruyama K, Regenfuss B, Hos D, Steven P, Heindl LM, Cursiefen C (2013) Novel anti(lymph)angiogenic treatment strategies for corneal and ocular surface diseases. Prog Retin Eye Res 34: 89-124.

Platonova N, Miquel G, Regenfuss B, Taouji S, Cursiefen C, Chevet E, Bikfalvi A (2013) Evidence for the interaction of fibroblast growth factor-2 with the lymphatic endothelial cell marker LYVE-1. Blood 1217: 1229-1237.

Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, Albrecht B, Bartholdi D, Beygo J, Di Donato N, Dufke A, Cremer K, Hempel M, Horn D, Hoyer J, Joset P, Ropke A, Moog U, Riess A, Thiel CT, Tzschach A, Wiesener A, Wohlleber E, Zweier C, Ekici AB, Zink AM, Rump A, Meisinger C, Grallert H, Sticht H, Schenck A, Engels H, Rappold G, Schrock E, Wieacker P, Riess O, Meitinger T, Reis A*, Strom TM* (2012) Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380: 1674-82.

Hoyer J, Ekici AB, Endele S, Popp B, Zweier C, Wiesener A, Wohlleber E, Dufke A, Rossier E, Petsch C, Zweier M, Gohring I, Zink AM, Rappold G, Schrock E, Wieczorek D, Riess O, Engels H, Rauch A, Reis A (2012) Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability. Am J Hum Genet 90: 565-72.

Cursiefen C, Maruyama K, Bock F, Saban D, Sadrai Z, Lawler J, Dana R, Masli S (2011) Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. J Exp Med. 208:1083-92.

Abou Jamra R, Philippe O, Raas-Rothschild A, Eck SH, Graf E, Buchert R, Borck G, Ekici A, Brockschmidt FF, Nothen MM, Munnich A, Strom TM, Reis A, Colleaux L (2011) Adaptor protein complex 4 deficiency causes severe autosomal-recessive intellectual disability, progressive spastic paraplegia, shy character, and short stature. Am J Hum Genet 88: 788-95.

Regenfuss B, Onderka J, Bock F, Hos D, Maruyama K, Cursiefen C (2010) Genetic heterogeneity of lymphangiogenesis in different mouse strains. Am J Pathol 1771: 501-510.

Dietrich T, Bock F, Yuen D, Hos D, Bachmann BO, Zahn G, Wiegand S, Chen L, Cursiefen C (2010) Cutting edge: lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. J Immunol. 184:535-9.

Huffmeier U, Uebe S, Ekici AB, Bowes J, Giardina E, Korendowych E, Juneblad K, Apel M, McManus R, Ho P, Bruce IN, Ryan AW, Behrens F, Lascorz J, Bohm B, Traupe H, Lohmann J, Gieger C, Wichmann HE, Herold C, Steffens M, Klareskog L, Wienker TF, Fitzgerald O, Alenius GM, McHugh NJ, Novelli G, Burkhardt H, Barton A, Reis A (2010) Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. Nat Genet 42: 996-9.

Regenfuss B, Bock F, Parthasarathy A, Cursiefen C (2008) Corneal (lymph)angiogenesis–from bedside to bench and back: a tribute to Judah Folkman. Lymphat Res Biol. 6:191-201.

Rauch A, Thiel CT, Schindler D, Wick U, Crow YJ, Ekici AB, van Essen AJ, Goecke TO, Al-Gazali L, Chrzanowska KH, Zweier C, Brunner HG, Becker K, Curry CJ, Dallapiccola B, Devriendt K, Dörfler A, Kinning E, Megarbane A, Meinecke P, Semple RK, Spranger S, Toutain A, Trembath RC, Voß E, Wilson L, Hennekam R, de Zegher F, Dörr HG, Reis A. (2008) Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism. Science 319: 816-819.

Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D’Amore PA, Dana MR, Wiegand SJ, Streilein JW (2004) VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest. 113:1040-50.