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Arbeitsgruppen

Als universitäre Einrichtung sind wir neben einer hochqualitativen Patientenversorgung sowie der Ausbildung der kommenden Ärztegenerationen auch der der stetigen wissenschaftlichen Weiterentwicklung unseres Fachgebietes verpflichtet. In diesem Rahmen betreiben wir umfassende Grundlagenforschung in unseren speziell eingerichteten Laboratorien. Zudem sind wir daran interessiert unsere Erkenntnisse schnell unseren Patienten zugute kommen zu lassen. Aufgrund dessen führen wir umfangreiche eigene klinische Studien in unserer Klinik durch und beteiligen uns an national als auch international wichtigen Multicenterstudien. 

 

Informieren Sie sich im Folgenden über unsere wissenschaftlichen Arbeitsgruppen und deren Projekte

Thrombozyten und Inflammation (AG Prof. Meinrad Gawaz)

Research Interest

Our research group is interested in regulation of platelet-dependent inflammation. Platelets play a critical role in mediating inflammatory reactions at site of platelet accumulation and modulate disease development and progression. At present we concentrate on platelet release factors such as chemokines (CXCL12) and other inflammatory mediators (e.g. MIF, Gremlin1) and their interaction with corresponding chemokine receptors such as CXCR4 and CXCR7. The research project is funded by the Deutsche Forschungsgemeinschaft and is incorporated in our Research Consortium Klinische Forschergruppe „Platelets-Basic Mechanisms and Translational Implications“. One of our major focus is Translational Medicine and to develop novel diagnostic and therapeutic strategies.#

Wissenschaftliche Mitarbeiter

Dr. rer. nat. Mita Chatterjee

cand. Dr. rer. nat. Sandra Beck

cand. Dr. med. vet. Manuela Büttcher

cand. Dr. med. vet. Franziska Schlegel

 

Arbeitsgruppe Biosignalanalyse (AG PD Dr. Christine Meyer-Zürn)

Arbeitsgruppenleiter: PD Dr. Christine Meyer-Zürn

Wissenschaftliche Mitarbeiter:

Dr. Christian Eick

Dr. Martin Duckheim

Patrick Groga-Bada

Dr. Parwez Aidery

Dr. Nina Götz

Dr. Lars Mizera

Paul Helle

Katharina Klee

   

Nichtwissenschaftliche Mitarbeiter: Studienassistentin Jane Gollub

Promotionsstudenten:

Cand. med. C. Bensch

Cand. med.  L. Kittlitz

Cand. med.  K. Reinhardt

Cand. med.  L. Kaeselitz

Cand. med.  N. Fuhrmann

Cand. med. T. Rothaupt

Cand. med. A. Dollar

Cand. med.  S. Bauer

Cand. med. S. Mannes

Cand. med. V. Gehre

N. Harland

Intracellular Signaling in cardiovascular diseases (AG PD Dr. Oliver Borst)

1. Intracellular signaling in platelet activation and arterial thrombosis
Platelet adhesion to subendothelial collagen after plaque rupture results in increase
of cytosolic Ca2+ activity followed by Ca2+-dependent platelet activation, aggregation
and degranulation. Platelet activation leads to the development of acute arterial
thrombotic occlusions resulting in acute ischemic stroke or myocardial infarction. The
focus of our research group are intracellular signaling pathways in platelet activation.
Especially signaling downstream of phosphoinositide 3 kinase (PI3K) and regulation
of ion channels and transporters, which are crucial for platelet function, are
investigated. The identification of platelet signaling pathways not only has clinical
implications for diagnosis, but also for rationale drug design.

2. CXC/CX3C-dependent signaling in inflammatory cardiomyopathy (DCMi)
Inflammation of myocardium is caused by pathogens such a cardiotopic viruses and
non-pathogen-related inflammation and is associated with poor clinical prognosis
(heart failure, sudden cardiac death). Inflammatory signaling pathways are critical in
the development of DCMi. The current project focuses on the role of inflammatory
CXC/CX3C chemokines (SDF-1, CXCL16, fractalkine), their respective receptors
(CXCR4/-6/-7 and CX3CR1) and intracellular signaling in cardiomyocytes
downstream of these chemokine receptors for the pathogenesis of myocarditis/DCMi.
Identification of these mechanisms may offer novel targets and therapeutic strategies
to control the disease on an individualized basis.

3. PI3K-dependent signaling in vascular inflammation
Atherosclerosis is a chronic inflammatory disease of the arterial vessel wall. Vascular
inflammation and remodeling during atherogenesis require complex cellular signaling
in monocytes/macrophages infiltrating the vessel wall. We investigate intracellular
PI3K-dependent signaling in monocytes/macrophages migration and invasion
underlying lesion formation at early stages of atherosclerosis as well as MMP
production and plaque rupture at later stages to identify novel targets in prevention
and treatment of atherogenesis.

Group leader
Oliver Borst, MD

Department of Cardiology & Cardiovascular Medicine
University of Tübingen
E-mail: oliver.borst@med.uni-tuebingen.de
Phone: +49 7071 29 82888

 

Members
Patrick Münzer, PhD
Postdoctoral fellow

Britta Walker, PhD
Postdoctoral fellow

Malte Schaub, MD
Research associate

Roland Tegtmeyer, MD
Research associate

Sascha Geue
PhD student

Nada Alnaggar
MD student

Daniela Eissler
Technical assistant

 

Publications

 

Funding
Deutsche Forschungsgemeinschaft (DFG) KFO 274 “PI3 Kinase-dependent
regulation of ion chanals and carriers in platelets”.
Deutsche Forschungsgemeinschaft (DFG) BO3786/1-1 “CXC/CX3C chemokine
receptors and PI3K-dependent signaling pathways in the pathogenesis of
inflammatory cardiomyopathy (DCMi)”.
Deutsche Herzstiftung (F16/15)
Dr. Karl Kuhn Stiftung
Fortüne research programme (1934-0-0 and 2133-0-0).

 

Collaborators
Dr. Robert Ahrends, Leibniz Institute for Analytic Sciences (ISAS), Dortmund,
Germany.
Professor Leticia Quintanilla de Fend, Department of Pathology, University of
Tübingen, Germany.
Professor Johan Heemskerk, Department of Biochemistry, Cardiovascular Research
Institute Maastricht (CARIM), Maastricht University, 6200 MD Maastricht, The
Netherlands.
Professor Christoph Kleinschnitz, Department of Neurology, University of Essen,
Germany.
Professor Karin Klingel, Department of Physiology, University of Tübingen, Germany.
Professor Florian Lang, Department of Physiology, University of Tübingen, Germany.
Professor Martin Schaller, Department of Dermatology, University of Tübingen.
Professor Harald Schulze, Department of Experimental Biomedicine, Experimental
Hemostaseology, University of Würzburg, Germany.
Dr. René Zahedi, Leibniz Institute for Analytic Sciences (ISAS), Dortmund.
Prof. Lars Zender, Department of Gastroenterology, University of Tübingen,
Germany.


Experimentelle Herzinsuffizienz (AG Dr. Michael Gramlich)

Ein weiterer Schwerpunkt der Grundlagenforschung am universitären Herzzentrum Tübingen liegt in der in der Entwicklung neuer therapeutischer Optionen für die Herzschwäche (Herzinsuffizienz).

Wir haben hierfür Patienten mit vererbter Herzinsuffizienz auf krankheitsverursachende Mutationen untersucht. Dabei konnten wir erstmals Mutation im sogenannten Titin als molekulargenetische Krankheitsursache identifizieren, einem Strukturprotein der Herz- und Skelettmuskulatur mit wichtigen Funktionen für den kontraktilen Apparat.

Wir haben ein Mausmodell generiert, welches eine menschliche Titin-Mutation imitiert. Die Titin-Mäuse entwickeln das Vollbild einer Herzinsuffizienz, und sind somit ein gutes Mittel, um den Verlauf der menschlichen Erkrankung untersuchen zu können. Wir verfügen damit außerdem über die Möglichkeit, neue therapeutische Strategien am Mausmodell zu erproben, und können damit Rückschlüsse auf die Behandlung betroffener Menschen schließen.

Ein Beispiel für einen solchen innovativen Therapieansatz ist die Verwendung sogenannter “Antisense-Oligonukleotide” (AO). AOs sind in der Lage, spezifisch an bestimmte Bereiche der DNA zu binden und dann die Ablesung des genetischen Kodes zu verändern. In einer multinationalen Zusammenarbeit mit Arbeitsgruppen aus Deutschland, den Niederlanden und Australien ist es gelungen, einen AO zu entwerfen, der die Ablesung von Titin-Mutationen blockiert. Somit entsteht ein Titin, das die krankheitsverursachende Mutation nicht mehr trägt. Das wurde bereits am Herzzentrum Tübingen erfolgreich am Mausmodell getestet. Eine klinische Studie zur Behandlung am Menschen ist geplant. Hiermit stünde zum ersten Mal ein kausal-therapeutischer Ansatz zur Behandlung der Herzinsuffizienz zur Verfügung.

Beteiligte Wissenschaftler:

Dr. med. Michael Gramlich, Arbeitsgruppenleiter

Qifeng Zhou, PhD Student

Jonathan Marquardt, MD Student

Julia Kelley Hahn, MD Student

Janine Saynisch, MD Student

Annalena Bornheimer, MD Student

Cardioimmunology (AG Jun. Prof. Harald Langer)

 

PI: Jun. Prof. Harald Langer, MD

Research focus: Cardioimmunology, platelet functions beyond thrombosis,

innate immunity, angiogenesis

Clinical focus: Interventional Cardiology, Coordinator MitraClip program

Phone: 07071-29 82907

E-Mail: harald.langer@med.uni-tuebingen.de

 

 

Topics:

- cell specific aspects of innate immunity in cardiovascular

  disease – in vivo models and translational aspects

 

- platelets beyond thrombosis – contribution to

  inflammation and tissue remodelling (KFO 274 – Platelets

  basic mechanisms and translational applications)

- antigen presenting cells in vascular inflammation and

  atherosclerosis (Lichtenberg Professorship)

- the complement system and vascular inflammation/

  angiogenesis

- neurovascular inflammation

- heart failure and innate immunity

- translational aspects of interventional therapy for mitral

  regurgitation

 

Research focus

Our team is interested in molecular and translational aspects of cardiovascular diseases. In particular, we try to understand the immunology of cardiovascular pathologies with focus on vascular inflammation and cells of the innate immune system. We apply integrated approaches from in vitro cell systems to in vivo mouse models and seek to transfer our results to relevant clinical questions with diagnostic or therapeutic implications.

As mouse models we investigate mechanisms in atherosclerosis, vascular injury and angiogesis using transgenic mice or mice with genetic deficiencies. Moreover, we apply in vivo models to assess cell specific mechanisms and study cell types important for inflammation such as platelets or dendritic cells. Importantly, wen try to transfer bench findings to clinical settings such as acute coronary syndrom, acute or chronic heart failure.

Atherosclerosis ApoE-/- mouse

Dendritic cells (DCs), ELMI

 

Team

Marcus Olbrich, PostDoc

Sonja Ebenhoech

Frederic Emschermann

Manuela Sauter

Rebecca Schleicher

Ying Ying Zhang

 

Technician

Sarah Gekeler

 

Clinical cardiologists

Dr. med. Johannes Patzelt

 

Medical Students

cand. med. Henry Nording

cand. med. Matthias Mezger

cand. med. Philipp Maier

cand. med. Joel Niethammer

 

Previous students

Dr. med. Eva Rett

Dr. med. Gregor Braun

Dr. med. Reinhard Sauter

 

Selected Publications

Todt F, Cakir Z, Reichenbach F, Emschermann F, Lauterwasser J, Kaiser A, Ichim G, Tait SW,

Frank S, Langer HF, Edlich F. Differential retrotranslocation of mitochondrial Bax and Bak. EMBO

J. 2015 Jan 2;34(1):67-80. Epub 2014 Nov 5.

 

Chatterjee M, Borst O, Walker B, Fotinos A, Vogel S, Seizer P, Mack A, Alampour-Rajabi S, Rath

D, Geisler T, Lang F, Langer HF, Bernhagen J, Gawaz M. Macrophage migration inhibitory factor

limits activation-induced apoptosis of platelets via CXCR7-dependent Akt signaling. Circ Res.

2014 Nov ;115(11):939-49. Epub 2014 Sep 29.

 

Lonsdorf AS, Kraemer BF, Fahrleitner M, Schoenberger T, Gnerlich S, Ring S, Gehring S,

Schneider SW, Kruhlak MJ, Meuth SG, Nieswandt B, Gawaz M, Enk AH, Langer HF.

Engagement of αIIbβ3 (GPIIb/IIIa) with ανβ3 mediates interaction of melanoma cells with

platelets - a connection to hematogeneous metastasis. J Biol Chem. 2012. 287:2168-2178. Epub

2011 Nov 18.

 

Stellos K, Sauter R, Fahrleitner M, Grimm J, Stakos D, Emschermann F, Panagiota V, Gnerlich

S, Perk A, Schönberger T, Bigalke B, Langer HF#, Gawaz M.# Binding of oxidized-LDL on

circulating platelets is increased in patients with acute coronary syndromes and induces platelet

adhesion on vascular wall in vivo. Arterioscler Thromb Vasc Biol, 2012 Aug;32(8):2017-20.

Epub 2012 Jun 14

 

Langer HF, Choi EY, Zhou H, Schleicher R, Chung KJ, Tang Z, Göbel K, Bdeir K, Chatzigeorgiou

A, Wong C, Bhatia S, Kruhlak MJ, Rose JW, Burns JB, Hill KE, Qu H, Zhang Y, Lehrmann E,

Becker KG, Wang Y, Simon DI, Nieswandt B, Lambris JD, Li X, Meuth SG, Kubes P, Chavakis T.

Platelets Contribute to the Pathogenesis of Experimental Autoimmune Encephalomyelitis. Circ

Res. 2012;110(9):1202-10. Epub 2012 Mar 27.

 

Langer HF, Chung KJ, Orlova VV, Choi EY, Kaul S, Kruhlak MJ, Alatsatianos M, Deangelis RA,

Roche PA, Magotti P, Li X, Economopoulou M, Rafail S, Lambris JD, Chavakis T. Complement-

mediated inhibition of neovascularization reveals a point of convergence between innate

immunity and angiogenesis. Blood. 2010;116:4395-4403. Epub 2010 Jul 12.

 

Economopoulou M *, Langer HF *, Celeste A, Orlova VV, Choi EY, Ma M, Vassilopoulos A,

Callen E, Deng C, Bassing CH, Boehm M, Nussenzweig A, Chavakis T: Histone H2AX is integral

to hypoxia-driven neovascularization. Nat Med 2009;15:553-558. * equal contribution

Choi EY, Chavakis E, Czabanka MA, Langer HF, Fraemohs L, Economopoulou M, Kundu RK,

Orlandi A, Zheng YY, Prieto DA, Ballantyne CM, Constant SL, Aird WC, Papayannopoulou T,

Gahmberg CG, Udey MC, Vajkoczy P, Quertermous T, Dimmeler S, Weber C, Chavakis T: Del-1,

an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment.

Science 2008;322:1101-1104.

 

Stellos K, Langer H, Daub K, Schoenberger T, Gauss A, Geisler T, Bigalke B, Mueller I, Schumm

M, Schaefer I, Seizer P, Kraemer BF, Siegel-Axel D, May AE, Lindemann S, Gawaz M: Platelet-

derived stromal cell-derived factor-1 regulates adhesion and promotes differentiation of human

CD34+ cells to endothelial progenitor cells. Circulation 2008;117:206-215.

 

Langer HF, Haubner R, Pichler BJ, Gawaz M: Radionuclide imaging: a molecular key to the

atherosclerotic plaque. J Am Coll Cardiol 2008;52:1-12.

 

Langer HF, Daub K, Braun G, Schonberger T, May AE, Schaller M, Stein GM, Stellos K,

Bueltmann A, Siegel-Axel D, Wendel HP, Aebert H, Roecken M, Seizer P, Santoso S,

Wesselborg S, Brossart P, Gawaz M: Platelets recruit human dendritic cells via Mac-1/JAM-C

interaction and modulate dendritic cell function in vitro. Arterioscler Thromb Vasc Biol

2007;27:1463-1470.

 

Langer H, May AE, Daub K, Heinzmann U, Lang P, Schumm M, Vestweber D, Massberg S,

Schonberger T, Pfisterer I, Hatzopoulos AK, Gawaz M: Adherent platelets recruit and induce

differentiation of murine embryonic endothelial progenitor cells to mature endothelial cells in vitro.

Circ Res 2006;98:e2-10.

 

Gawaz M, Langer,H, May,AE. Platelets in inflammation and atherogenesis. J Clin Invest

115:3378-3384.

 

 

Scientific Awards

2014 Spokesperson 2nd period KFO 274 of the DFG (H. Langer)

 

2014 2. poster award at the International Platelet Meeting of the KFO 274 Tuebingen (H.

Nording)

 

2014 Otto-Hess award for the best poster presentation (2nd) of the German Cardiac Society

(DGK), (H. Nording)

 

2013 Eberhard-Betz poster award of the German Society of Atherosclerosis Research (DGAF),

(H. Nording)

 

2012 Poster award of Tuebingen Medical School research symposium (Medizinische Fakultät

Tübingen, H. Nording)

 

2012 Poster award 1st international platelet symposium, Tübingen (J. Patzelt)

 

2012 Rudi Busse Young Investigator Award of the (2nd) German Cardiac Society (DGK), (R.

Sauter)

 

2011 Lichtenbergrpofessorship of the Volkswagenfoundation (H. Langer)

Coordinator KFO 274 of the DFG (H. Langer)

 

2009 Fellow Award of Research Excellence (FARE) of the National Institute of Health (NIH),

(H. Langer)

 

2007 Research Award of the County Rheinland-Pfalz for the replacement or reduction of

animal experiments(H. Langer)

 

PostDoc Stipend German Academy of Sciences (H. Langer)

 

Karin-Nolte Research Award (H. Langer)

 

2006 Ursula-M.-Händel Tierschutzpreis of the German Research Foundation (H. Langer)

 

Pfizerstipendium of the German Society for Cardiology (H. Langer)

 

2005 Poster award of the Südwestdeutsche Gesellschaft für Innere Medizin (H. Langer)

August Wilhelm und Liselotte Becht-Research Award of the German foundation for heart

research (H. Langer)

 

2004 G. Schettler-Award of the German association for research in atherosclerosis (H. Langer)

 

 

Myocardial inflammation (PD Dr. Peter Seizer)

Basic research:

- role of Cyclophilins for cardiovascular diseases

- myocardial and vascular inflammation

- platelets and platelet-monocyte interaction

- regulation of Matrix Metalloproteinases

Clinical research:

- association of inflammation and arrhythmias

- zero fluoroscopy ablation

- novel drug targets for inflammatory cardiomyopathy

The Team:

- Saskia von Ungern-Sternberg, PhD-student

- Dr. David Heinzmann, Postdoc

- Klaudia Posavec, technician

Medical students:

- Henrik Sturhan

- Christian Heck

- Moritz Nöthel

- Stefan Fuß

- Veronika Bucher

Cyclophlin A (green) in inflammatory cardiomypathy.

Cyclophlin A (green) in inflammatory cardiomypathy.

Research needs a Future – The Tübingen Research Campus

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