PAGE 15 DR MARTINA SCHMIDT 1 PERSONAL DATA NAME

“GLORIA ANAHÍ MARTINA SOBRE JURADO DE ENJUICIAMIENTO” N° 31
CURRICULUM VITAE INFORMAZIONI PERSONALI ZETA MARTINA V IALE MONZA
DOTTORANDA MARTINA GALLI TUTOR PROF CARLO SOTIS TITOLO DELLA

EMBARGO 1230PM CET SUNDAY 19 MAY 2013 ASTON MARTIN’S
FINANSŲ SEKTORIAUS PLĖTOTĖS STRATEGIJA EUGENIJA MARTINAITYTĖ DOCENTĖ GRUPĖS VADOVĖ
IME I PREZIME OCJENA BAJLO MARIJA 3 BUDAN MARTINA

L E B E N S L A U F

Page 15 Dr. Martina Schmidt

1 Personal data

Name Martina Schmidt

Date/Place of birth 13 December, 1963, Gelsenkirchen, Germany

Marital status married

Addresses private van Eedenlaan 14, 9752 GK Haren, The Netherlands

+31 - 50 - 7078163 phone

+31 - 6 - 5575 7924 mobile

professional Professor of Molecular Pharmacology

Rosalind Franklin Fellow

Department of Molecular Pharmacology

University of Groningen, Anton Deusinglaan 1

9713 AV Groningen, Netherlands

phone: +31 - 50 - 363 3322

Fax: +31 - 50 - 363 6908

[email protected]

2 Education / Degrees

1970 - 1974 Elementary school, Herten

1974 - 1983 Gymnasium, Herten

May 1983 Gymnasium Examination

1983 - 1989 Study Biology, Ruhr-Universität Bochum

February 1989 Master’s Degree Biology

1989 - 1992 Graduate student in the Institut für Physiologische Chemie, Ruhr-Universität Bochum, Promotor Prof. Dr. L.M.G. Heilmeyer Jr., Charakterisierung von Phosphatidylinositol 4-Kinasen und Phosphatidyl-inositol 4-Phosphat 5-Kinasen aus Rinderhirn

December 1992 Ph.D. Degree (graduation to Dr. rer. nat., cum laude)

June 1999 Fachpharmakologin of the Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie (DGPT)

December 2000 Habilitation (graduation to D.Sc.). Habilitationsarbeit: Molekulare Mechanismen der Phospholipase D-Stimulation durch membranständige Rezeptoren

February 2001 Venia legendi in Pharmacology and Toxicology

3 Academic employment

Post-doc fellow, Institut für Physiologische Chemie,

Ruhr-Universität Bochum

1993 - 1998 Post-doc fellow, Institut für Pharmakologie, Universitätsklinikum Essen

1998 - 2001 wissenschaftliche Assistentin [C1], Institut für Pharmakologie, Universitätsklinikum Essen

2002 - 2004 wissenschaftliche Oberassistentin [C2], Institut für Pharmakologie, Universitätsklinikum Essen

December 2004 - December 2005 Visiting scientist, Dept. Pharmacology & Pharmacotherapy and Dept. Anatomy & Embryology, Academic Medical Center, University of Amsterdam

December 2005 Assistant Professor, Dept. of Molecular Pharmacology, University of Groningen

- September 2006 Associate Professor of Molecular Pharmacology (Adjunct-hoogleraar)

4 Awards and Distinctions

February 2002 Ruf for a C3-Professorship

"Pharmakologie und Toxikologie", Universität Freiburg, Germany, primo loco

August 2004 C3-Professorship

"Pharmakologie und Toxikologie", Universität Ulm, Germany, tertio loco

January 2005 Forschungsstipendium Deutsche Forschungsgemeinschaft, project Physiologische Rolle von Epac-Proteinen im kardiovaskulären System

June 2005 Ruf for a W2-Professorship

"Physiologische Chemie", Universität Halle, Germany, primo loco

September 2005 Rosalind Franklin Fellowship, University of Groningen

January 2006 Rosalind Franklin Penning, University of Groningen

October 2007 Organon Prijs voor Farmacologie

Additionals

Reviewer of grant proposals and manuscripts

- Cancer Research UK, Deutsche Forschungsgemeinschaft, Interne Forschungsförderung

Universitätsklinikum Essen, Scottish Hospital Endowments Research Trust

Biochemical Journal, Biochimica et Biophysica Acta, Brain Research, British Journal of Pharmacology, European Journal of Pharmacology, FEBS Letters, Immunobiology, Molecular Pharmacology, Nature Signaling Gateway, Naunyn-Schmiedeberg’s Archives of Pharmacology

Professional qualifications

March 1995 Course Radiation Safety (Fachkundegruppe S4.1)

September 1998 Qualification as Projektleiter (PL) und Beauftragte für die biologische Sicherheit (BBS) und Gentechnik-Sicherheitsverordnung

Juni 2007 Certificate cursus proefdierkunde

Membership professional societies

since 1996 Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie

since 1999 American Society for Biochemistry and Molecular Biology

since 2004 American Society for Microbiology

since 2004 Deutscher Hochschulverband

since 2004 Nederlandse Vereniging voor Farmacologie

since 2005 British Pharmacological Society

since 2006 Member of the School of Behavioral and Cognitive Neuroscience at the University Groningen

Professional service and management

Institut für Pharmakologie, Universitätsklinikum Essen

since 1995 Radiation safety officer

since 1998 Project and team leader (research group: 2 technicians, 1 post-doc fellow, 1-2 Ph.D. students)

1999 - 2000 Coordinator of the reconstruction of the radiation safety laboratory in cooperation with the Sicherheitstechnischer Dienst of the hospital

since 2001 Doctoral examination of graduate students

since 2001 Project leader of an S1-biohazard laboratory

since 2002 Project leader of an S2-biohazard laboratory

2002 - 2003 Coordinator of the installation of a radiation safety plus S2-biohazard laboratory in cooperation with the Sicherheitstechnischer Dienst and the Bau-Dezernat of the hospital (model project in the country Nordrhein-Westfalen, Germany)

Medical Faculty of the University Duisburg-Essen

since 2002 Contribution to the Forschungstag of the faculty

- Supervision of oral and poster presentations of Ph.D. students

- Member of the evaluation committee

since 2003 Tutor in the University Lecturer Training Course "Lehren Lernen" (Teach the Teachers), Medical Faculty of the University Duisburg-Essen in cooperation with the Zentrum für Hochschuldidaktik und Qualitäts-entwicklung

since 2004 Coordinator of the Female Mentor Network "Meduse" at the Medical Faculty of the University Duisburg-Essen, Foundation of the project MediMent (Medizin Mentoring)

since 2004 Member of the Lenkungsgruppe of the project MediMent. Tandem supervision of excellent female researchers

since 2004 Mentor in the project MediMent (Mentee: Dr. Heike Bruck)

since 2004 Member of the Zentrum für Medizinische Biotechnologie (ZMB) research networking platform. Initiation of new collaborations (Prof. Dr. E. Gulbins, Prof. Dr. B. Lefkau)

since 2004 Member of the Westdeutsches Tumorzentrum Essen eV (WTZE). Development of new research accents

Professional activities elsewhere

since 2002 Member of the poster evaluation committee at the annual Spring Meetings of the Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie, Johannes Gutenberg University, Mainz

Sept. 2004 Master class Graduate School of Behavioural and Cognitive Neurosciences (BCN), University of Groningen

Meetings

since 1998 Organization of Institute Seminars with invited speakers, Institut für Pharmakologie, Universitätsklinikum Essen.

since 2000 Chairman and discussion leader of program sessions at the annual Spring Meetings of the Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie, Johannes Gutenberg University, Mainz

Sept. 2005 Molecular Cardiology Seminar, AMC, The Netherlands

Regulation of cellular signaling by Tiam-1; Invited speakers:

Dr. John Collard, Div. Cell Biology, Netherlands Cancer Institute

Dr. Thomas Wieland, Institut für Pharmakologie und Toxikologie, University of Heidelberg

July 2008 EUPHAR 2008: Epac: A novel signaling factor in the pulmonary and cardiovascular system; Organizer: Dr. Martina Schmidt, Invited speakers:

Dr. Johannes Bos, Utrecht, The Netherlands; Dr. Stephen Yarwood, Glasgow, UK; Dr. Manueal Zaccolo, Padua, Italy, Dr. Martina Schmidt, Groningen, The Netherlands

Invitated lectures international meetings

5^th International symposium on receptor mechanisms, signal transduction and drug effects; Shizuoka, Japan

Symposium G-protein targets Experimental biology meeting, New Orleans

Professional activities University of Groningen and Dutch societies

since 2007 Editorial Board of the “Nederlandse Vereniging voor Farmacologie”

2008 - Editorial Board: Current Molecular Pharmacology

2008 - Editorial Board of Groningen Research Institute for Asthma and COPD

2008 - Member of the opleidings commissie farmacie at the University of Groningen

Collaborations

University Duisburg-Essen

Prof. Dr. Artur-Aron Weber, Pharmakologie: Signaling pathways in lymphoid cells

Prof. Dr. Ursula Rauen, Physiologische Chemie: Cold-induced apoptosis of the liver

Germany

PD Dr. Harald Genth, Toxikologie, MH Hannover: Bacterial toxins

PD Dr. Jörg Heller, Universitätsklinikum Bonn: Mechanisms of vascular hypocontractility by portal hypertension

Prof. Dr. Bernd Nürnberg, Pharmakologie, Universität Tübingen: Role of PI 3-kinase in the PLD response

Prof. Dr. Dieter Rosskopf, Pharmakologie, Universität Greifswald: PLC-and Epac siRNAs

Prof. Dr. Thomas Wieland, Pharmakologie & Toxikologie, Mannheim of the University Heidelberg: Regulation and physiological importance of PLD signaling in cardiomyocytes.

Netherlands

Prof. Dr. Johannes Bos, Physiological Chemistry, Utrecht: Physiological role of Epac signaling in whole animals

Dr. Maurice van den Hoff, Anatomy & Embryology, Amsterdam: Reprogramming of cardiac fibroblasts into myocardial lineage

Prof. Dr. Martin Michel, Pharmacology & Pharmacotherapy, Amsterdam: Role of Epac and PLD in vascular smooth muscle contraction

Prof. Dr. Ulrich Eisel, Molecular Neurobiology, Groningen: Pathways in the chronic inflammatory disorders Alzheimer’s dementia and COPD

Prof. Dr. Rob Henning, Clinical Pharmacology, Groningen: Exploting nature’s tricks: dissecting hibernation to limit organ damage

International

Prof. Dr. Li Han, Dept. Infection Control & Research, Beijing: Actin organization by cofilin and PLD during bacterial and viral infection

Prof. Dr. Susumo Seino, Kobe, Japan: Epac-deficient mice models

Dr. Lonny Levin, Cornell, USA: Soluble adenylyl cyclclase and immune cells

Dr. Alan Smrcka, Rochester, USA: Phospholipase C- and COPD

Dr. Manuela Zaccolo, Glasgow, UK: Spatio-temporal cAMP signaling in the airways

Dr. Stephen Yarwood, Glasgow, UK: Inflammatory mediator and Epac

6 Scientific publications and patent(s)

International (refereed) journals IF = Impact factor

[1] Schmidt, M., Varsányi, M., Thieleczek, R. & Heilmeyer Jr., L.M.G. (1993) Identification of a new 80 k isoform of phosphatidylinositol 4-phosphate 5-kinase from bovine brain. FEBS Lett. 325, 201-204. (IF=3.84)

[2] Schmidt, M., Hüwe, S.M., Fasselt, B., Homann, D., Rümenapp, U., Sandmann, J. & Jakobs, K.H. (1994) Mechanisms of phospholipase D stimulation by m3 muscarinic acetylcholine receptors. Evidence for involvement of tyrosine phosphorylation. Eur. J. Biochem. 225, 667-675. (IF=3.26)

[3] Wieland, T., Liedel, K., Kaldenberg-Stasch, S., Meyer zu Heringdorf, D., Schmidt, M. & Jakobs, K.H. (1995) Analysis of receptor-G protein interactions in permeabilized cells. Naunyn-Schmiedeberg´s Arch. Pharmacol. 351, 329-336. (IF=1.96)

[4] van Koppen, C.J., Lenz, W., Nunes, J.P.L., Zhang, C., Schmidt, M. & Jakobs, K.H. (1995) The role of membrane proximal threonine residues conserved among guanine-nucleotide-binding-protein-coupled receptors in internalization of the m4 muscarinic acetylcholine receptor. Eur. J. Biochem. 234, 536-541. (IF=3.26)

[5] Schmidt, M., Fasselt, B., Rümenapp, U., Bienek, C., Wieland, T., van Koppen, C.J. & Jakobs, K.H. (1995) Rapid and persistent desensitization of m3 muscarinic acetylcholine receptor-stimulated phospholipase D. Concomitant sensitization of phospholipase C. J. Biol. Chem. 270, 19949-19956. (IF=6.36)

[6] Schmidt, M., Bienek, C., van Koppen, C.J., Michel, M.C. & Jakobs, K.H. (1995) Differential calcium signalling by m2 and m3 muscarinic acetylcholine receptors in a single cell type. Naunyn-Schmiedeberg´s Arch. Pharmacol. 352, 469-476. (IF=1.96)

[7] Rümenapp, U., Geiszt, M., Wahn, F., Schmidt, M. & Jakobs, K.H. (1995) Evidence for ADP-ribosylation-factor-mediated activation of phospholipase D by m3 muscarinic acetylcholine receptor. Eur. J. Biochem. 234, 240-244. (IF=3.26)

[8] Gehrmann, T., Vereb, G., Schmidt, M., Klix, D., Meyer, H.E., Varsányi, M. & Heilmeyer Jr., L.M.G. (1996) Identification of a 200 kDa polypeptide as type 3 phosphatidylinositol 4-kinase from bovine brain by partial protein and cDNA sequencing. Biochim. Biophys. Acta 1311, 53-63. (IF=3.48)

[9] Schmidt, M., Rümenapp, U., Bienek, C., Keller, J., von Eichel-Streiber, C. & Jakobs, K.H. (1996) Inhibition of receptor signaling to phospholipase D by Clostridium difficile toxin B. Role of Rho proteins. J. Biol. Chem. 271, 2422-2426. (IF=6.36)

[10] Schmidt, M., Bienek, C., Rümenapp, U., Zhang, C., Lümmen, G., Jakobs, K.H., Just, I., Aktories, K., Moos, M. & von Eichel-Streiber, C. (1996) A role for Rho in receptor- and G protein-stimulated phospholipase C. Reduction in phosphatidylinositol 4,5-bisphosphate by Clostridium difficile toxin B. Naunyn-Schmiedeberg´s Arch. Pharmacol. 354, 87-94. (IF=1.96)

[11] Zhang, C., Schmidt, M., von Eichel-Streiber, C. & Jakobs, K.H. (1996) Inhibition by toxin B of inositol phosphate formation induced by G protein-coupled and tyrosine kinase receptors in N1E-115 neuroblastoma cells: Involvement of Rho proteins. Mol. Pharmacol. 50, 864-869. (IF=5.08)

[12] Schmidt, M., Nehls, C., Rümenapp, U. & Jakobs, K.H. (1996) m3 Muscarinic receptor-induced and G_i-mediated heterologous potentiation of phospholipase C stimulation: Role of phosphoinositide synthesis. Mol. Pharmacol. 50, 1038-1046. (IF=5.08)

[13] Schmidt, M., Rümenapp, U., Nehls, C., Ott, S., Keller, J., von Eichel-Streiber, C. & Jakobs, K.H. (1996) Restoration of Clostridium difficile toxin-B-inhibited phospholipase D by phosphatidylinositol 4,5-bisphosphate. Eur. J. Biochem. 240, 707-712. (IF=3.26)

[14] Rümenapp, U., Schmidt, M., Wahn, F., Tapp, E., Grannass, A. & Jakobs, K.H. (1997) Characteristics of protein-kinase-C- and ADP-ribosylation-factor-stimulated phospholipase D activities in human embryonic kidney cells. Eur. J. Biochem. 248, 407-414. (IF=3.26)

[15] Keller, J., Schmidt, M., Hussein, B., Rümenapp, U. & Jakobs, K.H. (1997) Muscarinic receptor-stimulated cytosol-membrane translocation of RhoA. FEBS Lett. 403, 299-302. (IF=3.84)

[16] Lümmen, G., Virchow, S., Rümenapp, U., Schmidt, M., Wieland, T., Otto, T., Rübben, H. & Jakobs, K.H. (1997) Identification of G protein-coupled receptors potently stimulating migration of human transitional-cell carcinoma cells. Naunyn-Schmiedeberg´s Arch. Pharmacol. 356, 769-776. (IF=1.96)

[17] Schmidt, M., Lohmann, B., Hammer, K., Haupenthal, S., Voß, M., Nehls, C. & Jakobs, K.H. (1998) G_i- and protein kinase C-mediated heterologous potentiation of phospholipase C signaling by G protein-coupled receptors. Mol. Pharmacol. 53, 1139-1148. (IF=5.08)

[18] Rümenapp, U., Schmidt, M., Olesch, S., Ott, S., von Eichel-Streiber, C. & Jakobs, K.H. (1998) Tyrosine-phosphorylation-dependent and Rho-protein-mediated control of cellular phosphatidylinositol 4,5-bisphosphate levels. Biochem. J. 334, 625-631. (IF=4.28)

[19] Schmidt, M., Voß, M., Thiel, M., Bauer, B., Grannaß, A., Tapp, E., Cool, R.H., de Gunzburg, J., von Eichel-Streiber, C. & Jakobs, K.H. (1998) Specific inhibition of phorbol ester-stimulated phospholipase D by Clostridium sordellii lethal toxin and Clostridium difficile toxin B-1470 in HEK-293 cells. Restoration by Ral GTPases. J. Biol. Chem. 273, 7413-7422. (IF=6.36)

[20] Meyer zu Heringdorf, D., Lass, H., Alemany, R., Laser, K.T., Neumann, E., Zhang, C., Schmidt, M., Rauen, U., Jakobs, K.H. & van Koppen, C.J. (1998) Sphingosine kinase-mediated Ca²⁺ signalling by G-protein-coupled receptors. EMBO J. 17, 2830-2837. (IF=10.49)

[21] Vögler, O., Krummenerl, P., Schmidt, M., Jakobs, K.H. & van Koppen, C.J. (1999) RhoA-sensitive trafficking of muscarinic acetylcholine receptors. J. Pharmacol. Exp. Ther. 288, 36-42. (IF=4.34)

[22] *Schürmann, A., *Schmidt, M., Asmus, M., Bayer, S., Fliegert, F., Koling, S., Maßmann, S., Schilf, C., Subauste, M.C., Voß, M., Jakobs, K.H. & Joost, H.-G. (1999) The ADP-ribosylation factor (ARF)-related GTPase ARF-related protein binds to the ARF-specific guanine nucleotide exchange factor cytohesin and inhibits the ARF-dependent activation of phospholipase D. J. Biol. Chem. 274, 9744-9751. *Equal contribution. (IF=6.36)

[23] Schmidt, M., Voß, M., Oude Weernink, P.A., Wetzel, J., Amano, M., Kaibuchi, K. & Jakobs, K.H. (1999) A role for Rho-kinase in Rho-controlled phospholipase D stimulation by the m3 muscarinic acetylcholine receptor. J. Biol. Chem. 274, 14648-14654. (IF=6.36)

[24] Vögler, O., Nolte, B., Voss, M., Schmidt, M., Jakobs, K.H. & van Koppen, C.J. (1999) Regulation of muscarinic acetylcholine receptor sequestration and function by -arrestin. J. Biol. Chem. 274, 12333-12338. (IF=6.36)

[25] Meyer zu Heringdorf, D., Lass, H., Kuchar, I., Alemany, R., Guo, Y., Schmidt, M. & Jakobs, K.H. (1999) Role of sphingosine kinase in Ca²⁺ signalling by epidermal growth factor receptor. FEBS Lett. 461, 217-222. (IF=3.84)

[26] Keffel, S., Schmidt, M., Bischoff, A. & Michel, M.C. (1999) Neuropeptide-Y stimulation of extracellular signal-regulated kinases in human erythroleukemia cells. J. Pharmacol. Exp. Ther. 291, 1172-1178. (IF=4.34)

[27] Voß, M., Oude Weernink, P.A., Haupenthal, S., Möller, U., Cool, R.H., Bauer, B., Camonis, J.H., Jakobs, K.H. & Schmidt, M. (1999) Phospholipase D stimulation by receptor tyrosine kinases mediated by protein kinase C and a Ras/Ral signaling cascade. J. Biol. Chem. 274, 34691-34698. (IF=6.36)

[28] Oude Weernink, P.A., Schulte, P., Guo, Y., Wetzel, J., Amano, M., Kaibuchi, K., Haverland, S., Voß, M., Schmidt, M., Mayr, G.W. & Jakobs, K.H. (2000) Stimulation of phosphatidyl-inositol-4-phosphate 5-kinase by Rho-kinase. J. Biol. Chem. 275, 10168-10174. (IF=6.36)

[29] Oude Weernink, P.A., Guo, Y., Zhang, C., Schmidt, M., von Eichel-Streiber, C. & Jakobs, K.H. (2000) Control of cellular phosphatidylinositol 4,5-bisphosphate levels by adhesion signals and Rho GTPases in NIH 3T3 fibroblasts. Eur. J. Biochem. 267, 5237-5246. (IF=3.26)

[30] Schmidt, M., Frings, M., Mono, M.-L., Guo, Y., Oude Weernink, P.A., Evellin, S., Han, L. & Jakobs, K.H. (2000) G protein-coupled receptor-induced sensitization of phospholipase C stimulation by receptor tyrosine kinases. J. Biol. Chem. 275, 32603-32610. (IF=6.36)

[31] Rümenapp, U., Asmus, M., Schablowski, H., Woznicki, M., Han, L., Jakobs, K.H., Fahimi-Vahid, M., Michalek, C., Wieland, T. & Schmidt, M. (2001) The M₃ muscarinic acetylcholine receptor expressed in HEK-293 cells signals to phospholipase D via G₁₂ but not G_q type G proteins. Regulators of G proteins as tools to dissect pertussis toxin-resistant G proteins in receptor-effector coupling. J. Biol. Chem. 276, 2474-2479. (IF=6.36)

[32] Schmidt, M., Evellin, S., Oude Weernink, P.A., vom Dorp, F., Rehmann, H., Lomasney, J.W. & Jakobs, K.H. (2001) A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nature Cell Biol. 3, 1020-1024. (IF=20.65)

[33] Evellin, S., Nolte, J., Tysack, K., vom Dorp, F., Thiel, M., Oude Weernink, P.A., Jakobs, K. H., Webb, E., Lomasney, J.W. & Schmidt, M. (2002) Stimulation of phospholipase C- by the M₃ muscarinic acetycholine receptor mediated by cyclic AMP and the GTPase Rap2B. J. Biol. Chem. 277, 16805-16813. (IF=6.36)

[34] Wilde, C., Barth, H., Sehr, P., Han, L., Schmidt, M., Just, I. & Aktories, K. (2002) Interaction of the Rho-ADP-ribosylating C3 exoenzyme with RalA. J. Biol. Chem. 277, 14771-14776. (IF=6.36)

[35] Fahimi-Vahid, M., Gosau, N., Michalek, C., Han, L., Jakobs, K.H., Schmidt, M., Roberts, N., Avkiran, M. & Wieland, T. (2002) Distinct signaling pathways mediate cardiomyocyte phospholipase D stimulation by endothelin-1 and thrombin. J. Mol. Cell Cardiol. 34, 441-453. (IF=4.20)

[36] Gosau, N., Fahimi-Vahid, M., Michalek, C., Schmidt, M. & Wieland, T. (2002) Signalling components involved in the coupling of ₁-adrenoceptors to phospholipase D in neonatal rat cardiac myocytes. Naunyn-Schmiedeberg’s Arch. Pharmacol. 365, 468-476. (IF=1.96)

[37] Fetscher, C., Fleichmann, M., Schmidt, M., Krege, S. & Michel, M.C. (2002) M₃ muscarinic receptors mediate contraction of human urinary bladder. Br. J. Pharmacol. 136, 641-644. (IF=3.33)

[38] Heneweer, C., Kruse, L.H., Kindhäuser, F., Schmidt, M., Jakobs, K.H., Denker, H.-W., Thie, M. (2002) Adhesiveness of human uterine epithelial RL95-2 cells for trophoblast: Rho protein regulation. Mol. Hum. Reprod. 8, 1014-1022. (IF=3.07)

[39] Genth, H., Schmidt, M., Gerhard, R., Aktories, K. & Just, I. (2003) Activation of phospholipase D1 by ADP-ribosylated RhoA. Biochem. Biophys. Res. Commun. 302, 127-132. (IF=2.90)

[40] Stope, M.B., kunkel, C., Kories, C., Schmidt, M. & Michel, M.C. (2003) Differential agonist-induced regulation of human M₂ and M₃ muscarinic receptors. Biochem. Pharmacol. 66, 2099-2105. (IF=3.44)

[41] Oude Weernink, P.A., Meletiadis, K., Hommeltenberg, S., Hinz, M., Ishihara, H., Schmidt, M. & Jakobs, K.H. (2004) Activation of type I phosphatidylinositol-4-phosphate 5-kinase isoforms by the Rho GTPases, RhoA, Rac1, and Cdc42. J. Biol. Chem. 279, 7840-7849. (IF=6.36)

[42] Lutz, S., Freichel-Blomquist, A., Rümenapp, U., Schmidt, M., Jakobs, K.H. & Wieland, T. (2004) p63RhoGEF and GEFT are Rho-specific guanine nucleotide exchange factors encoded by the same gene. Naunyn-Schmiedeberg’s Arch. Pharmacol. 369, 540-546. (IF=1.96)

[43] vom Dorp, F., Sari, A.Y., Sanders, H., Keiper, M., Oude Weernink, P.A., Jakobs, K.H. & Schmidt, M. (2004) Inhibition of phospholipase C- by G_i-coupled receptors. Cell. Signal. 16, 921-928. (IF=4.74)

[44] Stope, M.B., vom Dorp, F., Szatkowski, D., Böhm, A., Keiper, M., Nolte, J., Oude Weernink, P.A., Rosskopf, D., Evellin, S., Jakobs, K.H. & Schmidt, M. (2004) Rap2B-dependent stimulation of phospholipase C-by epidermal growth factor receptor mediated by c-Src phosphorylation of RasGRP3. Mol. Cell. Biol. 24, 4664-4676. (IF=7.82)

[45] Keiper, M., Stope, M.B., Szatkowski, D., Böhm, A., Tysack, K., vom Dorp, F., Saur, O., Oude Weernink, P.A., Evellin, S., Jakobs, K.H. & Schmidt, M. (2004) Epac- and Ca²⁺-controlled activation of Ras and extracellular signal-regulated kinases by G_s-coupled receptors. J. Biol. Chem. 279, 46497-46508. (IF=6.36)

[46] Lutz, S., Freichel-Blomquist, A., Yang, Y., Rümenapp, U., Jakobs, K.H., Schmidt, M. & Wieland, T. (2005) The guanine nucleotide exchange factor p63RhoGEF  a specific link between G_q/11-coupled receptor signaling and RhoA. J. Biol. Chem. 280, 11134-11139. (IF=6.36)

[47] Hennenberg, M., Biecker, E., Trebicka, J., Jochem, K., Zhou, Q., Schmidt, M., Jakobs, K.H., Sauerbruch, T. & Heller, J. (2005) Defective RhoA/Rho-kinase signaling contributes to vascular hypocontractility and vasodilation in cirrhotic rats. Gastroenterology 130, 838-854. (IF=13.09)

[48] López de Jesús, M., Stope, M.B., Oude Weernink, P.A., Börgermann, C., Ananaba, V.N., Michel, M.C., Jakobs, K.H. & Schmidt, M. (2006) Cyclic AMP-dependent and Epac-mediated activation of R-Ras by G proteins-coupled receptors. Involvement of R-Ras in receptor-mediated stimulation of phospholipase D. J. Biol. Chem. J. Biol. Chem. 281, 21837-21847. (IF=6.36)

[49] Vogt, A., Lutz, S., Rümenapp, U., Han, L., Jakobs, K.H., Schmidt, M. & Wieland, T. (2007) Regulators of G protein signalling 3 redirects prototypical G_i-coupled receptors from Rac to Rho activation. Cell. Signal. 19, 1229-1237. (IF=4.74)

[50] Barendrecht, M.M., Mulders, A.C.M., van der Poel, H., van den Hoff, M., Schmidt, M. & Michel, M.C. (2007) Role of transforming growth factor  in rat bladder smooth muscle cell proliferation. J. Pharmacol. Exp. Ther. 322, 117-122. (IF=4.34)

[51] Gkoumassi, E., Dröge, M.J., Dekkers, B.G.J., Elzinga, C.R.S., Schmidt, M., Meurs, H., Zaagsma, J. & Nelemans, S.A. (2007) Virodhamine and CP55,940 modulate cAMP production and IL-8 release in human bronchial epithelial cells. Br. J. Pharmacol. 151, 1041-1048 (IF=3.33)

[52] Han, L., Stope, M.B., López de Jesús, M., Oude Weernink, P.A., Urban, M., Wieland, T., Rosskopf, D., Jakobs, K.H. & Schmidt, M. (2007) Phospho-cofilin directly interacts with and stimulates receptor-controlled phospholipase D1. EMBO J. 26, 4189-4202. (IF=10.46)

[53] Nunes, R.O., Schmidt, M., Dueck, G., Baarsma, H., Halayko, A.J., Kerstjens, H.A., Meurs, H., Gosens, R. (2008) The GSK-3/-catenin signaling axis in airway smooth muscle: Role in mitogenic signaling. Am. J. Physiol. Lung Cell Mol. Physiol. 294, 1110-1118.

[54] Nijholt, I., Dolga, A.M., Vieth, T., Ostroveanu, A., de Bruyn, M., Luiten, P.G.M., Schmidt, M. & Eisel, U.L.M. (2008) Neuronal AKAP150 coordinates PKA and Epac mediated PKB/Akt phosphorylation. Cell. Signal .20, 1715-1724.

[55] Grandoch, M., Oude Weernink, P.A., Weber, A.-A., Kajobs, K.H. & Schmidt, M. (2009) B cell receptor-induced growth arrest and apoptosis in WEHI-231 cells immature B lymphoma cells involve cyclic AMP and Epac proteins. Cell. Signal. 21, 609-621.

[56] Gkoumassi, E., Dekkers, B.G.J., Dröge, M.J., Elzinga, C.R.S., Hasenbosch, R.E., Meurs, H. S.A. Nelemans, Schmidt, M. & Zaagsma, J. (2009) Virodhamine and CP55,940 modulate cAMP production and IL-8 release in human bronchial epithelial cells. Naunyn-Schmiedeberg’s Arch. Pharmacol., DOI 10.1007/s00210-009-0406-z

[57] Grandoch, M., Bujok, V., Fleckenstein, D., Schmidt, M., Fischer, J.W. & Weber, A.-A. (2009) Epac inhibits apoptosis of human leukocytes. J. Leuk. Biol., in press.

Books

[1] Vereb, G., Schmidt, M., Klix, D., Varsányi, M. & Heilmeyer Jr., L.M.G. (1992) Isolation and characterization of phosphatidylinositol 4-kinase isozymes from bovine brain. Springer-Verlag NATO ASI Series Vol. 76, pp. 167-171.

[2] Schmidt, M., Vereb, G., Varsányi, M., Klix, D., Dreefs, C.E. & Heilmeyer Jr., L.M.G. (1992) Renaturation of phosphatidylinositol 4- and phosphatidylinositol 4-phosphate 5'-kinases following polyacrylamide gelelelectrophoresis in presence of SDS. Studies on their substrate binding requirements using synthetic substrate analogues. Springer-Verlag NATO ASI Series Vol. 76, pp. 197-200.

[3] Schmidt, M., Rümenapp, U., Zhang, C., Keller, J., Lohmann, B. & Jakobs, K.H. (1997) Receptor regulation of phospholipases C and D. Springer-Verlag NATO ASI Series Vol. 101, pp. 199-209.

[4] Schmidt, M., Oude Weernink, P.A., vom Dorp, F., Stope, M.B. & Jakobs, K.H. (2004) Mammalian phospholipase C. Advances in Molecular and Cell Biology (van der Vusse GJ ed) Vol 33, Lipobiology pp. 433-453, Elsevier Science, Amsterdam.

Review articles

[1] Rümenapp, U., Schmidt, M., Geiszt, M. & Jakobs, K.H. (1996) Participation of small GTP-binding proteins in m3 muscarinic acetylcholine receptor signalling to phospholipase D and C. Prog. Brain Res. Vol. 109, 209-216.

[2] Schmidt, M., Rümenapp, U., Keller, J., Lohmann, B. & Jakobs, K.H. (1997) Regulation of phospholipase C and D activities by small molecular weight G proteins and muscarinic receptors. Life Sci. 60, 1093-1100.

[3] Oude Weernink, P.A., Schmidt, M. & Jakobs, K.H. (2004) Regulation and cellular roles of phosphoinositide 5-kinases. Eur. J. Pharmacol., 500, 87-99.

[4] Peters, S.L.M., Schmidt, M. & Michel, M.C. (2006) Rho kinase: a target for treating urinary incontinence. Trends Pharmacol. Sci. 27, 492-497.

[5] Oude Weernink, P.A., Han, L., Jakobs, K.H. & Schmidt, M. (2006) Dynamic phospholipid signaling by G protein-coupled receptors. Biochim. Biophys. Acta. 1768, 888-900.

[6] Schmidt, M., Sand, C., Jakobs, K.H., Michel, M.C. & Oude Weernink, P.A. (2007) Epac and the cardiovascular system. Curr. Opin. Pharmacol. 7, 193-200.

[7] Oude Weernink, P.A., López de Jesús, M. & Schmidt, M. (2007) Phospholipase D signaling: orchestration by PIP₂and small GTPases. Naunyn-Schmiedeberg’s Arch. Pharmacol. 374, 399-411.

[8] Schaafsma, D., Roscioni, S.S., Meurs, H. & Schmidt, M. (2008) Monomeric G proteins as signal transducers in airway (patho)physiology. Cell. Signal. 20, 1705-1714.

[9] Gosens, R., Roscioni, S.S., Dekkers, B.G., Pera, T., Schmidt, M., Schaafsma, D., Zaagsma, J., Meurs, H. (2008) Pharmacology of airway smooth muscle proliferation. Eur. J. Pharmacol. 585, 385-397.

[10] Gosens, R., Meurs, H., Schmidt, M. (2008) The GSK-3/beta-catenin axis in smooth muscle and its relationship with remodelling. Naunyn-Schmiedeberg’s Arch. Pharmacol. 378, 345-357185-191

[11] Roscioni, S.S., Elzinga, C.R.S. & Schmidt, M. (2008) Epac: effectors and biological functions. Naunyn-Schmiedeberg’s Arch. Pharmacol. 377, 345-357.

[12] M. Grandoch, Roscioni, S.S. & Schmidt, M. (2009) Epac: novel cAMP mediators in inflammatory pulmonary and neuronal dysfunction. Brit. J. Pharmacol., in revision.

Original manuscripts submitted/revision

[1] Gosens, R., Barsma, H.A., Heijink, I.H., Halayko, A.J., Meurs, H. & Schmidt, M. De novo synthesis of -catenin via H-Ras and MEK regulates airway smooth muscle growth. FASEB J.

[2] Roscioni, S.S., Kistemaker, L.E.M., Menzen, M., Elzinga, C.R.S., Gosens, R., Halayko, A.J., Meurs, H. & Schmidt, M. PKA and Epac cooperate to augment bradykinin-induced interleukin-8 release from human airway smooth muscle. Resp. Res.

[3] Sand, C., Börgermann, C., Oude Weernink, P.A., Mahlke, Y., Schwindenhammer, B., Weber, A.-A., & Schmidt, M. 8-pCPT-conjugated cyclic AMP analogs exert thromboxane receptor antagonistic properties. Biochem. Pharmacol.

[4] Ostroveanu, A., van der Zee, E., Eisle, U.L.M., Schmidt, M. & Nijholt, I. Exchange protein directly activated by cyclic AMP2 (Epac2) plays a specific and time-limited role in memory retrieval. Hippocampus, in revision.

[5] van Wijk, B., van den Berg, G., Abu-Issa, R., van der Velden, S., Schmidt, M., Ruijter, J.M., Kirby, M.L., Moorman, A.F.M. & van den Hoff, M.J.B. Epicardial cells separate from the myocardial lineage under influence of FGF-signaling via Mek1/2. Cir. Res., in revision.

Patent: Nijholt, I.M., Schmidt, M. (2008) "Modulation of memory function"; P85114US00

6 Acquisition of 2^nd and 3^rd-stream funding

1996 Deutsche Forschungsgemeinschaft, project Regulation der Phospholipase D durch Rezeptoren und GTPasen. 2 Ph.D. positions (BAT IIa/2) plus DM 180.000 for 3 years.

1998 Deutsche Forschungsgemeinschaft, project Rezeptor-induzierte Langzeit-Potenzierung der Phospholipase C-Stimulation. 1 Ph.D. position (BAT IIa/2), 1 technician (BAT Vc) plus DM 105.000 for 3 years.

1998 Recruitment of Ph.D. stipends from the Interne Forschungsförderung Essen. Up to now: 15 positions for medical students plus € 5.000 per project.

1999 Interne Forschungsförderung Essen, project Regulation der PIP₂-Synthese durch Rho, Rho-kinase und Rezeptoren. 2 positions for medical students plus DM 30.000 for 1 year.

1999 Deutsche Forschungsgemeinschaft, project Regulation der Phospholipase D durch Rezeptoren und GTPasen. 2 Ph.D. positions (2 BAT IIa/2), 1 technician (BAT Vc) plus DM 180.000 for 3 years.

2001 Interne Forschungsförderung Essen, project Charakterisierung eines neuen Signaltransduktionsweges von Membranrezeptoren zur Phospholipase C. 2 positions for medical students plus DM 38.000 for 1 year.

2002 Deutsche Forschungsgemeinschaft, project Rezeptor-induzierte Langzeit-Potenzierung der Phospholipase C-Stimulation. 1 Post-doc position (BAT IIa), 1 technician (BAT Vb) plus € 61.355 for 3 years.

2003 Fonds der Chemischen Industrie im Verband der Chemischen Industrie eV, € 3.000 plus travel expenses.

2003 Interne Forschungsförderung Essen, project Aktivierung von Phospholipasen in Lymphozyten - Funktionelle Analysen nach systematischem RNA-Silencing. 2 positions for medical students plus € 19.717 for 1 year.

2004 Interne Forschungsförderung Essen, project Physiologische Rolle von Epac und Phospholipase C- im kardiovaskulären System. € 12.000 for 1 year.

2004 Post-doctoral fellowship for Dr. Maider López de Jesús from the Basque Goverment. € 52.000 for 2 years.

2005 Forschungsstipendium, Deutsche Forschungsgemeinschaft, project Physiologische Rolle von Epac-Proteinen im kardiovaskulären System. € 54.552 for 2 years.

2005 Deutsche Forschungsgemeinschaft, project Mechanismen der vaskulären Hypokontraktilität bei portaler Hypertension. Participant in the grant application of Dr. Jörg Heller, Universitätsklinikum Bonn. 1 Ph.D. position (BAT IIa/2) plus € 40.000 for 2 years.

2006 Deutsche Forschungsgemeinschaft, project Untersuchungen zum Mechanismus der kälteinduzierten Apoptose. Participant in the grant application of Dr. Ursula Rauen, Universitätsklinikum Essen (RA 960/1-3). 1 Ph.D. position (BAT IIa/2), 1 technician (BAT Vb) plus € 48.000 for 3 years.

2006 Rosalind Franklin Fellowship, start-up fund € 200.000

2006 Transfer of € 150.000 to Groningen. Deutsche Forschungsgemeinschaft, project Rezeptor-induzierte Langzeit-Potenzierung der Phospholipase C-Stimulation. 1 Post-doc position (BAT IIa), 1 technician (BAT Vb).

2006 Ubbo Emmius Scholarship, University of Groningen. Ph.D. position for 4 years.

2008 International Research Training Group GRK 880-3 Mannheim-Heidelberg-Groningen, Vascular medicine, project - (Patho)physiological role of NO/cGMP-induced RhoGEF17 activation in the vasculature. Principal Investigator with Dr. Susanne Lutz, Depart. Experimental & Clinical Pharmacology and Toxicology, Unversity of Heidelberg, Germany. 2 Ph.D. positions plus € 40.000 for 2 years.

2008 Ubbo Emmius Scholarship, University of Groningen, Ph.D. position for 4 years.

2008 Nederlands Astma Fonds, project The novel cAMP effector Epac: new avenues in the treatment of inflammation, tissue remodeling and airway narrowing in COPD. € 250.974 for 4 years, 1 Ph.D. position.

7 Teaching

Professionalization and didactic schooling attended

University Lecturer Training Course “Lehren Lernen” (Teach the Teachers), Advanced Training for University Teaching, Medical Faculty of the University Duisburg-Essen in cooperation with the Zentrum für Hochschuldidaktik und Qualitätsentwicklung:

- Sequel Unit 1 (04.07.2003): „Lehrveranstaltungen planen“

- Sequel Unit 2 (12.12.2003): „ Rhetorik, Präsentation, Einsatz von Medien“

Seminar (27/28.05.2004): „Personalführung und Konfliktmanagement“, Dr. C. Färber
Seminar (01.05.2004): „Potenzialanalyse und Laufbahnplanung“, Dr. C. Färber

Undergraduate teaching given

Institut für Physiologische Chemie, Ruhr-University Bochum

Practical courses and oral examinations in Physiological Chemistry for medical students (1989 -1992)

Institut für Pharmakologie, Faculty of Medicine, University Duisburg-Essen

Teaching of medical students:

Seminars in General and Systemic Pharmacology and Toxicology (1993-2005)

Adrenergic system and pharmacology of asthma bronchiale; Cholinergic agents, skeletal muscle relaxants and histamine; Vasodilators and antihypertensives; Treatment of heart failure and antiarrhythmic drugs; Haemostasis, thrombosis and diuretics; Antibiotics;
Opioid and non-opioid analgesic drugs; Thyroid agents, insulin and oral hypoglycemic agents; Corticosteroids and sex hormones; Antidepressants, sedatives & antipsychotic drugs.

Lectures in General Pharmacology and Toxicology (1999-2005)

Antiviral and antifungal agents; Immunosuppressive agents; Pharmacokinetics: Drug absorption, distribution, and elimination; Drug metabolism.

Problem-based Learning (2003-2005)

With the lecturer as mentor, students in small groups of 10 work out independently selected topics in pharmacology and toxicology, after having presented and discussed representative patient case studies.

Examination of undergraduate students (2004-2005)

Responsible for the entire organization and execution of the course General and Systemic Pharmacology and Toxicology, including programming, composing and judging the examination-papers.

Faculty of Medicine, University Duisburg-Essen

Doctoral examination of graduate students (2001- )

Tutor in the University Lecturer Training Course "Lehren Lernen" (2003-2005)

Coordinator of the University Female Mentor Network "Meduse" (2004- )

University of Groningen

Bachelor Postpropedeuse Farmacie / Farmaceutische Wetenschappen
Flexibel Bacheloropleiding Levenswetenschappen (propedeuse)

(Students of Biology, Pharmacy, Medical Biology, Medicine)

Algemene Farmacologie I (Introduction Physiology & Pharmacology, level 1)
Algemene Farmacologie II (Introduction Physiology & Pharmacology, level 2)
Course coordination & student lectures (5 ECTS)
Flexible Bacheloropleiding Levenswetenschappen (post-propedeuse)
Receptorpharmakologie
Course coordination & student lectures (5ECTS)
Master Farmacie / Farmaceutische Wetenschappen
Geneesmiddelgroepen: Tractus Circulatorius
Physiology & Pharmacology: Cardiovascular system, kidney, blood
Course coordination & student lectures (5 ECTS)
Caput Moleculaire Farmacologie (Master Farmacie)
Course coordination & student lectures (3 ECTS)
Participatie in Communicatie en Orientatie (Farmacologie)
Begeleiding Practicum Moleculaire Farmacologie
Begeleiding Hoofd- en Bijvakonderzoek (Bachelor & Master)
BCN International Master Course
Participatie in Genes, Brain, and Brain Functions

% time teaching

Duties and responsibilities in Teaching required about 30 % of my working hours.

Ph.D. Supervisor

Institut für Pharmakologie, Graduation University Duisburg-Essen, Faculty of Medicine

Dr. med. is about equivalent to a Dutch undergraduate master project

[1] Dr. med. Birgit Maria Fasselt (1993-1994) November 1995. Judgement: magna cum laude.

[2] Dr. med. Yuanjian Guo (1997-1999) May 1999. Judgement: magna cum laude.

[3] Dr. med. Markus Frings (1997-1998) March 2001. Judgement: magna cum laude.

[4] Dr. med. Stephan Haupenthal (1997-1998) September 2001. Judgement: magna cum laude.

[5] Dr. med. Kerstin Hammer (1997-1998) October 2001. Judgement: magna cum laude.

[6] Dr. med. Ursula Möller (1997-1998) November 2001. Judgement: magna cum laude.

[7] Dr. med. Christoph Nehls (1995) January 2002. Judgement: magna cum laude.

[8] Dr. med. Christine Bienek (1994-1995) May 2002. Judgement: cum laude.

[10] Dr. med. Marie-Luise Mono (1999) November 2002. Judgement: magna cum laude.

[11] Dr. med. Eva Tapp (1997) November 2002. Judgement: magna cum laude.

[12] Dr. med. Silke Bayer (1998) November 2002. Judgement: magna cum laude.

[13] Dr. med. Sibylle Eicken (1999-2001) May 2003. Judgement: cum laude.

[14] Dr. med. Christina Rother (1998-1999) May 2003. Judgement: magna cum laude.

[15] Dr. med. Karina Tysack (2001-2002) October 2004. Judgement: magna cum laude.

[16] Dr. med. Jan Nolte (2001-2002) October 2004. Judgement: magna cum laude.

[17] Dr. med. Felix Kindhäuser (2000-2001) October 2004. Judgement: cum laude.

[18] Dr. med. Melanie Asmus (1998) May 2005. Judgement: magna cum laude.

[19] Dr. med. Anja Böhm (2002) November 2005. Judgement: magna cum laude.

[20] Dr. med. Patrizia Caracciola (1999-2000) December 2005. Judgement: magna cum laude.

[21] Dr. med. Ayse Y. Sari (2001-2002) May 2006. Judgement: magna cum laude.

[22] Dr. med. Daniel Szatkowski (2002) November 2006. Stipendiary of the Studienstiftung des deutschen Volkes. Judgement: magna cum laude.

[23] Dr. med. Bernhard Limper (2008) Ocotber 2008, Jugdgement: cum laude.

[24] Dr. med. Martina Urban (2009) March 2009, Judgement: magna cum laude.

Institut für Pharmakologie, Graduation University Duisburg-Essen,

Departments of Biology, Chemistry and Pharmacy

Dr. rer. nat. is equivalent to a Dutch graduate thesis

[1] Dr. rer. nat. Ulrich Rümenapp (1993-1996) December 1996. Judgement: summa cum laude. Fritz-Külz-Preis für Experimentelle Pharmakologie of the Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie.

[2] Dr. rer. nat. Matthias Voß (1996-2000) September 2000. Judgement: magna cum laude.

[3] Dr. rer. nat. Sandrine Evellin (1999-2003) January 2003. Judgement: magna cum laude.

[4] Dr. rer. nat. Li Han (2000-2003) March 2003. Judgement: magna cum laude.

[5] Dr. rer. nat. Melanie Keiper (2002-2005) March 2005. Judgement: magna cum laude.

Ph.D. External Examiner

Faculty of Medicine, University Duisburg-Essen

[1] Dr. med. Norman Putzki (2002) Judgement: magna cum laude.

[2] Dr. med. Andrea Waβmuth (2002) Judgement: cum laude.

[3] Dr. med. Bertrand Prévôt (2003) Judgement: magna cum laude.

[4] Dr. med. Mirabutaleb Samimi (2003) Judgement: cum laude.

[5] Dr. med. Thomas-Heinrich Vockel (2003) Judgement: cum laude.

[6] Dr. med. Dörthe Zupancic (2003) Judgement: cum laude.

[7] Dr. med. Petronela Nemesszeghyova (2003) Judgement: magna cum laude.

[8] Dr. med. Anne Flörcken (2004) Judgement: magna cum laude.

[9] Dr. med. Julia Fee Landscheidt (2004) Judgement: magna cum laude.

Elsewhere

[1] Dr. rer. nat. Stéphanie Boutillier (2002) University of Strasbourg. Judgement: magna cum laude.

[2] Dr. Angela Hommel (2007) Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke. Judgement: magna cum laude.

Ph.D. Supervisor-University Groningen

[1] Dr. Mark Boterman (2006) Groningen. Molecular Pharmacology. Judgement: cum laude.

[2] Dr. Harm Maarsingh (2006) Groningen. Molecular Pharmacology. Judgement: cum laude.

[3] Dr. Dedmer Schaafsma (2007) Groningen. Molecular Pharmacology. Judgement: cum laude.

[4] Dr. Martin Hennenberg (2007) Groningen. Molecular Pharmacology. Judgement: cum laude.

[5] Dr. Effimia Gkoumassi (2007) Groningen. Molecular Pharmacology. Judgement: cum laude.

[6] Dr. Amalia M. Dolga (2008) Groningen. Judgement: cum laude.

[7] cand. Dr. Sarah Roscioni (2006-) Airway smooth muscle transition and its impact on the progession of COPD.

[8] cand. Dr. Fatemeh Talaei (2008) Epac: A key role in hibernation?

Supervision of Postdoctoral fellows and guest researchers

[1] Dr. Frank vom Dorp (2001-2003)

[2] Dr. Christoph Börgermann (2004-2005)

[3] Dr. Maider López de Jesús (2004-). Stipendiary of the Basque Government.

[4] Dr. Christina Michalek (2002)

[5] Dr. Peter Hein (2002)

[6] Dr. Carola Heneweer (2002-2004)

[7] Dr. Christoph Altmann (2003)

[8] Dr. Martin Hennenberg (2004-)

[9] Dr. Harm Maarsingh (2006-)

[10] Dr. Reinoud Gosens (2006-)

[11] Dr. Ingrid Nijholt (2006-)

9 Research concept

My scientific record verifies our achievements and reputation in the molecular regulation of phospholipases, G proteins, and lipid and protein kinases by membrane receptors, and the discovery of novel signaling cascades in various cellular systems. It is becoming increasingly clear that signaling pathways are executed after clustering of molecular partners in defined subcellular compartments (signalosomes), that enables cells to exert highly specialized tasks. Actually, our goal for the future is to unravel the organization of the recently discovered signaling components within functional units by biochemical, molecular and cell biological methods. A second goal will be to further define how these novel pathways regulate physiological processes in cell, tissue and organ systems. We have directed our attention to chronic inflammatory disorders, as evidence exist for a role of our signaling components (Epac, PLD) in vascular smooth muscle cells, neuronal cells, immune cells as well as cardiomyocytes and airway smooth muscle cells. Many devastating diseases, e.g. cancer, type-II diabetes mellitus, Alzheimers’s dementia, cardiovascular and airway diseases (heart failure, cardiac arrhythmia, developmental defects, asthma and COPD) are associated with defective or derailed signaling processes, and research into the control of these processes clearly is of great public and social importance as well. The proposed goals clearly demand a multidisciplinary proceeding, and continuing and new collaborations with local, national and international groups will be increasingly important to finish successful projects and to continue the strong and high-ranking publication output.

Regulation of phospholipase D by cofilin: impact on the actin cytoskeleton

We have elucidated signaling pathways from the M₃ muscarinic receptor that lead to the activation of PLD. One pathway consists of the sequential activation of Rho-kinase and LIM-kinase by RhoA, resulting in phosphorylation of the actin depolymerizing factor cofilin. Phosphorylated cofilin directly interacts with and stimulates PLD1, disclosing a novel and exciting function of cofilin and a direct connection between PLD and cytoskeleton organization (Han et al, EMBO J., 26, 4189-4202). Many cellular tasks depend on dynamic actin reorganization, and PLD/cofilin interaction likely has a major impact on cellular functioning. The role of PLD will be primarily analyzed in cells from the cardiovascular system, but further promising possibilities and avenues are feasible, including the role of PLD/cofilin in cytoskeletal rearrangements in vascular/airway smooth muscle remodeling, and cellular adhesiveness.

Role of PLC potentiation in neuronal cells

It is almost axiomatic in neuroscience that postsynaptically induced long-term potentiation is a cellular substrate of learning and memory formation. However, the signaling processes that support this form of neuronal plasticity are incompletely understood. In contrast to most other signaling cascades that are down-regulated upon continued receptor stimulation, we found that repeated triggering of membrane receptors resulted in enhanced signaling by PLC. This interesting phenomenon likely reflects a form of cellular memory, and we therefore started to characterize the molecular mechanism of PLC potentiation. Recently, we demonstrated for the first time that Epac2 specifically modifies memory retrieval (Ostroveanu et al, Hippocampus, in revision), and this research line delivered a patent "Modulation of memory function"; P85114US00.

Regulation and cellular roles of phospholipase C-

We have successfully defined several signaling pathways from membrane receptors towards the recently identified PLC- isoform (e.g. Schmidt et al, Nat. Cell Biol., 3, 1020-1024). Studies into the involvement of PLC- in other cellular processes and specialized cell types are initiated, and preliminary results indicate that PLC stimulation by the antigen receptor in B lymphocytes is dependent on Epac proteins and Rap GTPases (Grandoch et al., Cell. Signal., 21, 609-621). As PLC- is likely to represent a molecular switch between Ras and ERK1/2, which are reported to be implicated in the bone morphogenetic protein (BMP) receptor pathway, our studies may further elucidate signaling processes during stages of embryonic heart development (van Dijk et al., Circ. Res., in revision).

Physiological role of Epac in chronic inflammatory disorders

The function of cells in the cardiovascular and neuronal system (cardiomyocytes, vascular smooth muscle cells and neuronal cells) is strictly controlled by receptors that regulate the activity of ion channels as well as the generation of the universal second messengers cAMP and Ca²⁺. cAMP typically stimulates PKA, but recently, Epac proteins were identified as novel cAMP effectors, which function as activators for Rap GTPases. As mentioned above, we have characterized a novel and exciting signaling pathway from G_s-coupled receptors to PLC-, and these studies established Epac proteins as essential cellular switches that connect changes in cAMP levels with cellular Ca²⁺ homeostasis. With our powerful tools (combining in vitro and in vivo models), we collected recently evidence that Epac driven signaling is of importance in physiological systems that likely depend on cAMP/Ca²⁺ interactions or Rap GTPases, for instance integrin-mediated cell adhesion, cell migration (tumorigenesis and cancer), embryonic heart development, neuronal diseases and chronic inflammatory disorders. In particular, we gain insight into the spatio-temporal organization of cyclic AMP signaling by identifying signaling complexes composed of AKAP-PKA-Epac (Nijholt et al., Cell. Signal., 20, 17150-1724), and focus on the impact of Epac signaling in B and T lymphocytes (Grandoch et al., Cell. Signal., 21, 609-612; Grandoch et al., J. Leuk. Biol., in press). In addition, Epac modulates hibernation and COPD (Nederlands Astma Fonds project). Of interest the impact of Epac on hibernation, 'wintersleep', that makes animals cycle from low body temperature (full rewarming, without organ damage). Evidently, this trick of nature may be exploited in 'harsh' conditions in man. Limitations in time or metabolic-rate are beneficial in many medical conditions: severe trauma, organ transplantation, cardiac arrest. Molecular mechanisms of hibernation are largely unexplored, but seem to be related to Epac.

KONTAKT MARTINA KUBEŠOVÁ SDRUŽENÍ TEREZA HAŠTALSKÁ 17 PRAHA 1
LATEIN FORUM 64 25 HYPERTEXT IM LATEINUNTERRICHT MARTINA ADAMI
MARLBROOK PRIMARY LITTLE DEWCHURCH CE ST MARTIN’S

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