Lymphangiogenomics

 

 
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IDENTIFICATION OF GENES AND CELLULAR PATHWAYS INVOLVED IN LYMPHANGIOGENESIS AND ANGIOGENESIS

 

 

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Last Update: August 26, 2008

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  

 

 

 

  

 

 

 

 

Phenotypes are often influenced by multiple genetic loci which are called quantitative trait loci (QTLs). One of our goals is to identify and characterize complex traits influencing lymphangiogenesis by using QTL analysis in mice.

As many crucial genetic networks and biochemical pathways implicated in human disease are conserved in zebrafish, the zebrafish embryo represents an excellent in vivo bioassay system for the identification and functional validation of biomedically relevant genes and novel drug targets. A selection of genes, identified in a previously performed morpholino knock-down screen to yield vascular defects, will be further validated and characterized.

We will also analyse the involvement and therapeutic potential of adult stem cells in lymphatic vessel formation and growth, addressing the following questions: differentiation of murine MAPCs into lymphatic endothelial cells (LECs); potential of MAPCs, singly or in combination with lymphangiogenic growth factor therapy, to induce functional lymphatic vessels in wild type mice and in lymphedemic Chy mice.

 

 

Responsible for this project:

 

 

Dr. Peter Carmeliet

Center for Transgene Technology and Gene Therapy

Flanders Interuniversity Institute for Biotechnology

Herestraat 49

3000 Leuven, Belgium

Phone: +32 16 345 774

Fax: +32 16 345 990

E-mail: Peter.Carmeliet(at)med.kuleuven.be

Homepage: www.vib.be/Research

 

 

Selected recent publications:

  1. Ny A, Koch M, Vandevelde W, Schneider M, Fischer C, Diez-Juan A, Neven E, Geudens I, Maity S, Moons L, Plaisance S, Lambrechts D, Carmeliet P, Dewerchin M. Role of VEGF-D and VEGFR-3 in developmental lymphangiogenesis, a chemicogenetic study in Xenopus tadpoles. Blood, in press.
     

  2. Lambrechts D, Storkebaum E, Carmeliet P. VEGF: necessary to prevent motoneuron degeneration, sufficient to treat ALS? Trends Mol Med 10:275-282, 2004.
     

  3. Belting M, Dorrell MI, Sandgren S, Aguilar E, Ahamed J, Dorfleutner A, Carmeliet P, Mueller BM, Friedlander M, Ruf W. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med 10:502-509, 2004.
     

  4. Maes C, Stockmans I, Moermans K, Van Looveren R, Smets N, Carmeliet P, Bouillon R, Carmeliet G. Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival. J Clin Invest 113:188-199, 2004.
     

  5. Compernolle V, Brusselmans K, Franco D, Moorman A, Dewerchin M, Collen D, Carmeliet P. Cardia bifida, defective heart development and abnormal neural crest migration in embryos lacking hypoxia-inducible factor-1alpha. Cardiovasc Res 60:569-579, 2003.
     

  6. Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al-Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang-Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 34:383-394, 2003.
     

  7. Rakic JM, Lambert V, Devy L, Luttun A, Carmeliet P, Claes C, Nguyen L, Foidart JM, Noel A, Munaut C. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci 44:3186-3193, 2003.
     

  8. Reijerkerk A, Mosnier LO, Kranenburg O, Bouma BN, Carmeliet P, Drixler T, Meijers JC, Voest EE, Gebbink MF. Amyloid endostatin induces endothelial cell detachment by stimulation of the plasminogen activation system. Mol Cancer Res 1:561-568, 2003.
     

  9. Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, Lambrechts D, Kroll J, Plaisance S, De Mol M, Bono F, Kliche S, Fellbrich G, Ballmer-Hofer K, Maglione D, Mayr-Beyrle U, Dewerchin M, Dombrowski S, Stanimirovic D, Van Hummelen P, Dehio C, Hicklin DJ, Persico G, Herbert JM, Communi D, Shibuya M, Collen D, Conway EM, Carmeliet P. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9:936-943, 2003.
     

  10. Lambert V, Munaut C, Carmeliet P, Gerard RD, Declerck PJ, Gils A, Claes C, Foidart JM, Noel A, Rakic JM. Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type I: implications for clinical trials. Invest Ophthalmol Vis Sci 44:2791-2797, 2003.
     

  11. Brusselmans K, Compernolle V, Tjwa M, Wiesener MS, Maxwell PH, Collen D, Carmeliet P. Heterozygous deficiency of hypoxia-inducible factor-2alpha protects mice against pulmonary hypertension and right ventricular dysfunction during prolonged hypoxia. J Clin Invest 111:1519-1527, 2003.
     

  12. Levi M, Dorffler-Melly J, Reitsma P, Buller H, Florquin S, van der Poll T, Carmeliet P. Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice. Blood 101:4823-4827, 2003.
     

  13. Stalmans I, Lambrechts D, De Smet F, Jansen S, Wang J, Maity S, Kneer P, von der Ohe M, Swillen A, Maes C, Gewillig M, Molin DG, Hellings P, Boetel T, Haardt M, Compernolle V, Dewerchin M, Plaisance S, Vlietinck R, Emanuel B, Gittenberger-de Groot AC, Scambler P, Morrow B, Driscol DA, Moons L, Esguerra CV, Carmeliet G, Behn-Krappa A, Devriendt K, Collen D, Conway SJ, Carmeliet P. VEGF: a modifier of the del22q11 (DiGeorge) syndrome? Nat Med 9:173-182, 2003.
     

  14. Luttun A, Tjwa M, Moons L, Wu Y, Angelillo-Scherrer A, Liao F, Nagy JA, Hooper A, Priller J, De Klerck B, Compernolle V, Daci E, Bohlen P, Dewerchin M, Herbert JM, Fava R, Matthys P, Carmeliet G, Collen D, Dvorak HF, Hicklin DJ, Carmeliet P. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8:831-840, 2002.
     

  15. Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, Plaisance S, Dor Y, Keshet E, Lupu F, Nemery B, Dewerchin M, Van Veldhoven P, Plate K, Moons L, Collen D, Carmeliet P. Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 8:702-710, 2002. Erratum in: Nat Med 8:1329, 2002.
     

  16. Mattot V, Moons L, Lupu F, Chernavvsky D, Gomez RA, Collen D, Carmeliet P. Loss of the VEGF(164) and VEGF(188) isoforms impairs postnatal glomerular angiogenesis and renal arteriogenesis in mice. J Am Soc Nephrol 13:1548-1560, 2002.
     

  17. Luttun A, Carmeliet P. Genetic studies on the role of proteinases and growth factors in atherosclerosis and aneurysm formation. Ann NY Acad Sci 947:124-132, 2001.
     

  18. Brusselmans K, Bono F, Maxwell P, Dor Y, Dewerchin M, Collen D, Herbert JM, Carmeliet P. Hypoxia-inducible factor-2alpha (HIF-2alpha) is involved in the apoptotic response to hypoglycemia but not to hypoxia. J Biol Chem 276:39192-39196, 2001.
     

  19. Rajantie I, Ekman N, Iljin K, Arighi E, Gunji Y, Kaukonen J, Palotie A, Dewerchin M, Carmeliet P, Alitalo K. Bmx tyrosine kinase has a redundant function downstream of angiopoietin and vascular endothelial growth factor receptors in arterial endothelium. Mol Cell Biol 21:4647-4655, 2001.
     

  20. Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S, Theilmeier G, Dewerchin M, Laudenbach V, Vermylen P, Raat H, Acker T, Vleminckx V, Van Den Bosch L, Cashman N, Fujisawa H, Drost MR, Sciot R, Bruyninckx F, Hicklin DJ, Ince C, Gressens P, Lupu F, Plate KH, Robberecht W, Herbert JM, Collen D, Carmeliet P. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28:131-138, 2001.
     

  21. Carmeliet P, Moons L, Luttun A, Vincenti V, Compernolle V, De Mol M, Wu Y, Bono F, Devy L, Beck H, Scholz D, Acker T, DiPalma T, Dewerchin M, Noel A, Stalmans I, Barra A, Blacher S, Vandendriessche T, Ponten A, Eriksson U, Plate KH, Foidart JM, Schaper W, Charnock-Jones DS, Hicklin DJ, Herbert JM, Collen D, Persico MG. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7:575-583, 2001