Project 2 Modulators of LA

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

Summary

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 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 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.

Selected Key Publications of Project 2

Clahsen T, Hos D, Cursiefen C (2017) Lymphangiogenesis research in the eye: What’s the point? LymphForsch 1: 27-39

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 (2017) [New Therapeutic Approaches in Inflammatory Diseases of the Eye – Targeting Lymphangiogenesis and Cellular Immunity: Research Unit FOR 2240 Presents Itself]. Klinische Monatsblatter fur Augenheilkunde 234: 679-685

Bock F, Onderka J, Braun G, Schneider AC, Hos D, Bi Y, Bachmann BO, Cursiefen C (2016) Identification of Novel Endogenous Anti(lymph)angiogenic Factors in the Aqueous Humor. Investigative ophthalmology & visual science 57: 6554-6560

Ettle B, Kerman BE, Valera E, Gillmann C, Schlachetzki JC, Reiprich S, Buttner C, Ekici AB, Reis A, Wegner M, Bauerle T, Riemenschneider MJ, Masliah E, Gage FH, Winkler J (2016) alpha-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy. Acta neuropathologica 132: 59-75

Notara M, Refaian N, Braun G, Steven P, Bock F, Cursiefen C (2016) Short-Term Ultraviolet A Irradiation Leads to Dysfunction of the Limbal Niche Cells and an Antilymphangiogenic and Anti-inflammatory Micromilieu. Investigative ophthalmology & visual science 57: 928-39

Ahmed I, Buchert R, Zhou M, Jiao X, Mittal K, Sheikh TI, Scheller U, Vasli N, Rafiq MA, Brohi MQ, Mikhailov A, Ayaz M, Bhatti A, Sticht H, Nasr T, Carter MT, Uebe S, Reis A, Ayub M, John P et al. (2015) Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment. Human molecular genetics 24: 3172-80

Hos D, Schlereth SL, Bock F, Heindl LM, Cursiefen C (2015) Antilymphangiogenic therapy to promote transplant survival and to reduce cancer metastasis: what can we learn from the eye? Seminars in cell & developmental biology 38: 117-30

Notara M, Refaian N, Braun G, Steven P, Bock F, Cursiefen C (2015) Short-term uvb-irradiation leads to putative limbal stem cell damage and niche cell-mediated upregulation of macrophage recruiting cytokines. Stem cell research 15: 643-654

Regenfuss B, Dreisow ML, Hos D, Masli S, Bock F, Cursiefen C (2015) The Naive Murine Cornea as a Model System to Identify Novel Endogenous Regulators of Lymphangiogenesis: TRAIL and rtPA. Lymphatic research and biology 13: 76-84

Vasileiou G, Ekici AB, Uebe S, Zweier C, Hoyer J, Engels H, Behrens J, Reis A, Hadjihannas MV (2015) Chromatin-Remodeling-Factor ARID1B Represses Wnt/beta-Catenin Signaling. American journal of human genetics 97: 445-56

More Publications of Project 2

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 (2014) Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: The I-CAN study. Ophthalmology 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.