Friedrich Kapp, MD

Clinical Head of the Interdisciplinary Center for Vascular Anomalies

E: friedrich.kapp@uniklinik-freiburg.de
T: +49 (0)761 270-46211
F: +49 (0)761 270-46160

Division of Pediatric Hematology and Oncology
Department of Pediatrics and Adolescent Medicine
Medical Center – University of Freiburg
Mathildenstraße 1
79106 Freiburg
Germany

The zebrafish allows the study of the development of the vasculature. A) Two Tg(kdrl:GFP) zebrafish embryos at 12 somites showing mesodermal precursors. B) Formation of the caudal vein plexus, the Tg(kdrl:dsRed)+ endothelial cells form filopodia (arrows). C) Vasculature in the tail at 72 hpf, endothelial cells are red (Tg(kdrl:dsRed)), the circulating erythrocytes are green (Tg(LCR:GFP)).

 

Vascular anomalies represent a broad spectrum of rare diseases that include vascular tumors and vascular malformations. To enhance our understanding of the genetic framework of and the molecular mechanisms underlying vascular anomalies, we model these diseases in the zebrafish embryo. This allows us to study aberrant cellular processes during vascular development, to functionally test novels mutations identified in patients, and to test novel therapeutic approaches.

TEAM

  • Nagi Mahammadzade (PhD candidate in biology): Developmental timing in the formation of arteriovenous malformations; former IMBS Master student project: RIT1 as a novel gene in arteriovenous malformations
  • Johanna Cordes (MD student): SOS1 as a novel gene in arteriovenous malformations
  • Lena Wäsch (MD student): Effects of novel CDC42 mutations on hematopoiesis and interferon signaling; Interactions of blood stem cells and their niche
  • Salomé Brodd (MD student): Early genotyping to facilitate phenotypic observations in zebrafish embryos

Former lab members

  • Cora Beckmann (MD student): Modelling novel mutations in hematopoietic diseases; Publication
  • Jakob Siebert (MD student): Xenotransplantation of rhabdomyosarcoma cells into zebrafish embryos (collaboration with Dr. Simone Hettmer); Publication
  • Lorenz Bell (MD student): Modelling novel mutations in vascular malformations; Publication
  • Cedric Schneider (Dentistry student): Clinical research on coagulopathies in rare vascular malformations; Publication
  • Siddharth Bhardwaj (IMBS Master student): Intronic BRAF mutations as driver in an AVM-like lesion
  • Raquel Rosillo (IBMS Winter School rotational student)
  • Marie Kapla (MD student): Imaging of early neural development in PCH2 (collaboration with Dr. Wibke Janzarik)

RESEARCH THEMES

The genetic basis of vascular anomalies is only beginning to be understood via the identification of recurrently mutated genes. RAS-pathway mutations are often found in high-flow (arterio-venous) malformations, while low-flow malformations (venous and lymphatic malformations) are often caused by aberrations in the PIK3CA/mTOR-pathway. However, the downstream consequences of the mutations, the epigenetic changes and the abnormal processes leading to the development of vascular malformations remain largely unknown. This lack of knowledge hinders the development of novel, targeted therapeutics.

We recently have developed pipeline to assess the effect of mutations found in patients with vascular anomalies by mosaic endothelial-specific expression in the zebrafish embryo. We are studying the effect of different mutations in this system and are further refining its application in translational research. Using this model, we focus on the elucidating the underlying molecular mechanisms that control development and maintenance of the vascular malformations, and on establishing novel treatment options for severely affected patients.

FUNDING

EXCEL-Fellowship (sponsored by the Else-Kröner-Fresenius Foundation)

Faculty of Medicine, University of Freiburg

DFG-funded clinical study: SIPA-SOS: Sirolimus in Patients with Segmental Overgrowth Syndrome

COLLABORATIONS, CO-OPERATIONS AND NETWORKS

SELECTED RECENT PUBLICATIONS

Friedrich Kapp’s ORCID webpage can be found here: https://orcid.org/0000-0002-2729-6177

  • Andreoti TAA, Berg S, Holm A, Angerer M, Oberlin M, Foeldi E, Baumgartner I, Niemeyer CM, Rössle, J, Kapp FG, 2023. Complex Lymphatic Anomalies: Report on a Patient Registry Using the Latest Diagnostic Guidelines. Lymphat Res Biol. https://doi.org/10.1089/lrb.2022.0041
  • Kapp FG, Schneider C, Holm A, Glonnegger H, Niemeyer CM, Rößler J, Zieger B, 2022. Comprehensive Analyses of Coagulation Parameters in Patients with Vascular Anomalies. Biomolecules 12, 1840. https://doi.org/10.3390/biom12121840
  • Siebert J, Schneider M, Reuter-Schmitt D, Würtemberger J, Neubüser A, Driever W, Hettmer S, Kapp FG, 2022. Rhabdomyosarcoma xenotransplants in zebrafish embryos. Pediatr Blood Cancer e30053.
  • Holm A, te Loo M, Schultze Kool L, Salminen P, Celis V, Baselga E, Duignan S, Dvorakova V, Irvine AD, Boon LM, Vikkula M, Ghaffarpour N, Niemeyer CM, Rössler J, Kapp FG, 2021. Efficacy of Sirolimus in Patients Requiring Tracheostomy for Life-Threatening Lymphatic Malformation of the Head and Neck: A Report From the European Reference Network. Front. Pediatr. 9, 697960.
  • Bell LM, Holm A, Matysiak U, Driever W, Rößler J, Schanze D, Wieland I, Niemeyer CM, Zenker M, Kapp FG. Functional assessment of two variants of unknown significance in TEK by endothelium-specific expression in zebrafish embryos. Human Molecular Genetics, 2021 Jul
  • Rössler J, Baselga E, Davila V, Celis V, Diociaiuti A, El Hachem M, Mestre S, Haeberli D, Prokop A, Hanke C, Loichinger W, Quéré I, Baumgartner I, Niemeyer CM, Kapp FG. Severe adverse events during sirolimus “off label” therapy for vascular anomalies. Pediatric Blood & Cancer, 2021 Feb 13;e28936.
  • Kapp FG, Perlin JR, Hagedorn EJ, Gansner JM, Schwarz DE, O’Connell LA, Johnson NS, Amemiya C, Fisher DE, Wölfle U, Trompouki E, Niemeyer CM, Driever W, Zon LI. Protection From UV Light Is an Evolutionarily Conserved Feature of the Haematopoietic Niche. Nature 2018 558, 445–448
  • Piragyte I, Clapes T, Klein-Geltnik R, Yin N, Polyzou A, Langa Oliva X, Beckmann C, Lefkopoulos S , Theißen P, Wlodarski M, Van Essen D, Rambold A, Kapp FG, Mione M, Pearce E, Polyzos A, Trompouki E. A metabolic interplay co-ordinated by HLX balances hematopoietic stem cell stemness and differentiation. Nature Communications 2018 9, 3090
  • Patsch C, Challet-Meylan L, Thoma EC, Urich E., Heckel T, O’Sullivan, JF, Grainger SJ, Kapp, FG, Sun L, Christensen K, Xia Y, Florido MHC, He W, Pan W, Prummer M, Warren CR, Jakob-Roetne R, Certa U, Jagasia R, Freskgård PO, Adatto I, Kling D, Huang P, Zon LI, Chaikof EL, Gerszten RE, Graf M, Iacone R, Cowan CA. Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells. Nature Cell Biology 2015 Aug;17(8):994-1003