Wir suchen immer Doktorandinnen und Doktoranden - weitere Informationen und Kontakte finden Sie bei den jeweiligen Arbeitsgruppen.
Arbeitsgruppenleitung
- Prof. Dr. med. Hermann Haller
Wissenschaftliche Mitarbeiter
- Dr. rer. nat. Nelli Shushakova
- Dr. Christoph Schröder
- Dr. med. Heiko Schenk
- Dr. Florence Njau
- Uta Hillebrand
- Martin Reinhardt
- Carsten Lindschau
- Julia Kiyan, PhD.
- Sergey Tkachuk, PhD.
- Margret Patecki
- Dr. med. Klaus Stahl
Technische Assistenten
- Birgit Habermeier
- Frank Hausadel
- Petra Wübbolt-Lehmann
- Michaela Beese
Projektbeschreibung
Die Arbeitsgruppe beschäftigt sich mit den molekularen und zellulären Mechanismen der Gefäßwandschädigung. Dabei stehen die Erkrankungen des Endothels in der Mikrozirkulation im Vordergrund. Endothelzellen werden bereits frühzeitig in der Pathogenese von zahlreichen Krankheiten geschädigt. Es können Interaktionen (Adhäsion), Schädigung durch kardiovaskuläre Risikofaktoren oder immunologische Vorgänge dabei eine Rolle spielen. Das Endothel ist in vivo und in vitro schwierig zu untersuchen. Die Arbeitsgruppe beschäftigt sich mit Fragen der Endothelzelldifferenzierung, der Polarität von Endothelzellen sowie der langfristigen Veränderungen durch epigenetische Mechanismen. Von besonderem Interesse ist die Signaltranskription in Endothelzellen. Die Arbeitsgruppe beschäftigt sich seit Jahren mit Calcium- und Phospholipid–abhängigen Signaltransduktionsmechanismen, insbesondere der Proteinkinase C. es sind Knockout-Modelle für die meisten der PKC-Isoformen hergestellt werden. Es wird in tierphysiologischen und zellulären Modellen analysiert, welche Rolle diese PKC-Isoformen bei der Entstehung von Gefäß- und Nierenerkrankungen spielen. Insbesondere die Entstehung der diabetischen Nephropathie ist ein Schwerpunkt der Arbeitsgruppe.
Die Arbeitsgruppe verfügt über ein großes Methodenspektrum. Neben tierphysiologischen Untersuchungen in der Maus, Proteinurie, Bluthochdruck, Niereninsuffizienz, werden andere Modellsysteme wie Zebrafisch (siehe Arbeitsgruppe Schiffer) eingesetzt. Es werden primäre Zelllinien aus den Tiermodellen gewonnen und in vitro epigenetische Mechanismen sowie die Signaltransduktion von Proteinkinase-C-Isoformen untersucht.
Eine wichtige Fragestellung ist auch der Einsatz von spezifischen Inhibitoren der Proteinkinase-C bei renalen und kardiovaskulären Erkrankungen. Insbesondere Inhibitoren der Proteinkinase-C-Isoform alpha werden im Tiermodell eingesetzt bzw. in translationalen Experimenten bei Menschen untersucht.
Publikationen
Kontakt
We are an interdisciplinary group of intensivists with a wide background of nephrology, gastroenterology/hepatology as well as pulmonary medicine focusing on Translational Critical Care Medicine.
Our experimental focus lies on endothelial permeability, injury to the endothelial glycocalyx and microcirculatory dysfunction in critical illness.
As a clinical focus, we initiated several prospective studies that investigate novel treatment options for septic shock (EXCHANGE), ARDS (SPARE-14), non-occlusive mesenteric ischemia (REPERFUSE) and CAR-T-cell associated Cytokine release syndrome (CYTORELEASE-Ex).
From a translational aspect, we investigate from „bedside to bench“ in patients included in these studies the effect of extracorporeal treatment approaches on endothelial permeability, glycocalyx and microcirculation.
Principal Investigator team:
Prof. Dr. med. Sascha David is a nephrologist and intensivist. He holds positions both as the section chief of internal intensive care medicine at University Hospital Zürich, Switzerland and Hannover Medical School, where he continues his lab. He is the initiator of this group and has a broad spectrum of interest in endothelial pathology as well as translational sepsis reasearch.
Contact: david.sascha@mh-hannover.de , sascha.david@usz.ch
Dr. med. Klaus Stahl is a nephrologist and continues his education in gastroenterology and critical care medicine at Hannover Medical School. He mainly focuses on extracorporeal therapies for sepsis, cytokine release syndrome, acute- and acute-on-chronic liver failure as well as non-occlusive mesenteric ischemia.
Contact: stahl.klaus@mh-hannover.de
Dr. med. Benjamin Seeliger is specializing in respiratory and critical care medicine at Hannover Medical School with a special focus on interstitial lung diseases and acute respiratory distress syndrome and ECMO support.
Contact: seeliger.benjamin@mh-hannover.de
Dr. med. Julius Schmidt is a nephrologist and intensivist at Hannover Medical School. He is mainly interested in drug pharmacokinetics and the effects of extracorporeal treatment modalities in the care of critically ill patients.
Contact: schmidt.julius@mh-hannover.de
Experimental Staff:
- Yvonne Nicolai (RA): Lab manager supervising all experiments and teaching students
- Temitayo O Idowu (Msc): PhD student (Mechanisms of Tie2 cleavage) – experiments ongoing
- Valerie Etzrodt (cand. med.): Struc Med thesis (Role of MIR155 in endothelial permeability) – experiments ongoing
- Philipp Gronski (cand. med.): Doctoral thesis (Injury to the endothelial glycoclayx in severe COVID-19) – experiments ongoing
- Thorben Pape (cand. med.): Struc Med Thesis (Pharmaceutical off-target effects on Ang-2) – experiments ongoing
- Janine Hauschild (cand. med.): Doctoral thesis (Dual Ang2 VEGF inhibition in murine sepsis) – manuscript published
- Eva Hachmeister (cand. med.): Doctoral thesis (Role of statins on Ang2 (ARDSnet trial) – thesis writing
- Hannah Knaup (cand. med.): Doctoral thesis (Plasmaexchange in sepsis) – reviews completed / summa cum laude
- Jennifer Retzlaff: Struc Med Thesis (Flunarizine - Ang2) – reviews completed / summa cum laude
- Ramin Rokhzan: Struc Med thesis / Biomedical Exchange Program (Boston, Harvard Medical School) - reviews completed / summa cum laude
Clinical Staff:
- Dilek Cansiz: Medical documentation assistant – Spare14 ARDS/Sepsis Registry (LOGO) Coordination und Data-management
- Nina Rittgerodt (cand. med.): Doctoral thesis (REPERFUSE) - recruiting
- Philipp Wand (cand. med.): Doctoral thesis (EXCHANGE) - recruiting
- Robert Friedrich (cand. med.): Student co-worker / Project: anticoagulation in VV-ECMO – manuscript in preparation
- Jan Fuge MPH, Datamanagement (Pneumology): continuous generous IT and statistical support
Experimental Research:
Our group is interested in molecular mechanisms regulating endothelial barrier function in response to inflammation. We have been focusing on the Angiopoietin (Angpt) / Tie ligand receptor system over the last ten years. Tie2 is a transmembrane receptor tyrosinekinase that is essential for embryonic vessel development. In mature organisms its function shifts toward maintenance of endothelial homeostasis and reaction to insults. Angpt-1 is the major circulating Tie2 agonist that promotes protective anti-permeability signals, whereas Angpt-2 has antagonistic properties. Our group was the first to prove in a murine knockout model that Angpt-2 directly contributes to sepsis morbidity and mortality.
Based on this finding we have conducted a series of experiments exploring potential therapeutic strategies (antibody, siRNA etc.) to eliminate or block the injurious Angpt-2 protein in sepsis models. We are also conducting drug repurposing screens to identify potential off-target Angpt-2 regulators (T. Pape).
Recently, we have gained much attention in the regulation of the Tie2 receptor expression per se and are currently working on the underlying mechanisms of posttranslational Tie2 modifications (T. Idowu).
MicroRNAs might be involved in Tie2 processing in disease as well so that we are studying the potential of MIRs in inflammatory diseases (V. Etzrodt).
We are also interested in the interaction between endothelial cells and pericytes – both with regard to Angiopoietin signaling and bioactive adrenomedullin (bioADM) (P. Gronski).
Another focus lies in the investigation of the endothelial glycocalyx both in vivo (SDF imaging) and in-vitro (endothelial microperfusion chip model). As injury of the endothelial glycocalyx can be found early in critical illness and substantially contributes to endothelial dysfunction we, together with the AG Haller, investigate regulation of glycocalyx degradation both in septic shock (U. Hillebrand) as well as severe COVID-19 (P. Gronski).
Clinical Research:
A major interest of our clinical research is focused on questions regarding medical critical care mostly in the context of sepsis and septic shock. In a prosepctive non-randomized pilot study, we could demonstrate that early therpeutic plasma exchange (TPE) improves hemodynamics and endothelial permeability as well as reduced inflammatory cytokines in patients with severe septic shock (EXCHANGE Pilot, published). We are currently conducting a randomized controlled trial together with the University Hopsital Bonn (Dr. Bode/Putensen) to analyse the role of TPE in early septic shock on hemodynamic stability (EXCHANGE I, NCT04231994). Funding for a German multicenter RCT with a clinically meaningful endpoint is under review at the DFG (EXCHANGE II).
In order to better understand sepsis and ARDS we are collecting human biomaterials (bronchoalveolar lavage and blood) and clinical characteristics of sepsis +/- ARDS patients. This Sepsis and ARDS Register (SPARE-14) will help to translate experimental findings of our basic research group from bench to bedside.
Support of non-intubated patients with both chronic and acute lung failure with extra-corporeal membrane oxygenation, termed Awake ECMO, is an innovative strategy that has been first established at Hannover medical school as it potentially completely avoids the multiple potential side effects of invasive ventilation. We continue to explore this strategy in selected patient cohorts such as patients with PcP associated ARDS. ECMO support in special patient cohorts, e.g. patients with diffuse alveolar hemorrhage, and conditions, e.g. heparin free ECMO, are further clinical interests of our group.
We are also conducting research on extracorporeal cytokine removal in patients treated with CAR-T cells suffering from severe cytokine release syndrome (CytoreleaseEx, NCT04048434). This project is financially supported by Cytosorbents.
We are currently running a prospective observational trial to analyze intra-arterial prostaglandine infusion into the superior mesenteric artery in non-occlusive mesenteric ischemia (NOMI) patients (REPERFUSE, NCT04235634) . This project is conducted together with our Department of Interventional Radiology.
High volume TPE in acute liver failure has been shown to improve survival. We investigate more feasible low volume TPE strategies in both acute- and acute on chronic liver failure.
Collaborations:
- Prof. Samir Parikh, MD, BIDMC and Harvard Medical School, Boston, MA, USA
- Paul van Slyke, PhD, Vasomune Therapeutics, Toronto, Canada
- PD Dr. Christian Bode, Operative Intensive Care Medicine, University Hospital Bonn
- Dr. Andrew Aswani, MD, PhD, Critical Care Medicine and Anesthesia, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK
- Prof. Dr. Hermann Haller and Dr. Yulia Kiyan, Nephrology, Hannover Medical School
- Prof. Dr. Marius Hoeper and Dr. Olaf Wiesner, Respiratory and Critical Care Medicine, Hannover Medical School
- Prof. Dr. Antje Prasse, Department of Respiratory Medicine at Hannover Medical School and Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover
- Prof. Dr. Jan T Kielstein, Medical Clinic V, Nephrology, Rheumatology, Blood Purification, Academic Teaching Hospital Brunswick
- Prof. Dr. Christian Könecke, Hematology and Oncology, Hannover Medical School
- Prof. Dr. rer. nat. Ulrich Maus PhD, Experimental Pneumology, Hannover Medical School
- PD Dr. Jan Hinrichs, Interventional Radiology, Hannover Medical School
- Prof. Dr. Ulrich Budde, Hemostasiology, University Hospital Hamburg
- Prof. Dr. Malgorzata Wygrecka, PhD, Biochemistry, University Gießen
- Dr. Markus Busch, Dr. Andrea Schneider and PD Dr. Benjamin Maasoumy, Gastroenterology and Hepatology, Hannover Medical School
Funding:
Our experiments are currently supported by the „Deutsche Forschungsgemeinschaft“ (DFG), the „Deutsche Lungenzentrum“ (DZL) and others.
Where to meet us:
Members of our group are actively contributing to the annual meeting of the following societies:
- European Society of Intensive Care Medicine (ESICM)
- European Respiratory Society (ERS)
- Deutsche Gesellschaft für Internistische Intensiv- und Notfallmedizin (DGIIN)
- Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin (DIVI)
- SepsisUpdate
Most recent publications:
Experimental:
- Hauschildt J, Schrimpf C, Thamm K, Retzlaff J, Idowu TO, von Kaisenberg C, et al. Dual Pharmacological Inhibition of Angiopoietin-2 and VEGF-A in Murine Experimental Sepsis. Journal of vascular research. 2020;57(1):34-45.
- Kiyan Y, Tkachuk S, Kurselis K, Shushakova N, Stahl K, Dawodu D, et al. Heparanase-2 protects from LPS-mediated endothelial injury by inhibiting TLR4 signalling. Scientific reports. 2019;9(1):13591.
- Thamm K, Schrimpf C, Retzlaff J, Idowu TO, van Meurs M, Zijlstra JG, et al. Molecular Regulation of Acute Tie2 Suppression in Sepsis. Critical care medicine. 2018;46(9):e928-e36.
- Retzlaff J, Thamm K, Ghosh CC, Ziegler W, Haller H, Parikh SM, et al. Flunarizine suppresses endothelial Angiopoietin-2 in a calcium - dependent fashion in sepsis. Scientific reports. 2017;7:44113.
- Ghosh CC, David S, Zhang R, Berghelli A, Milam K, Higgins SJ, et al. Gene control of tyrosine kinase TIE2 and vascular manifestations of infections. PNAS 2016;113(9):2472-7.
- Ghosh CC, Thamm K, Berghelli AV, Schrimpf C, Maski MR, Abid T, et al. Drug Repurposing Screen Identifies Foxo1-Dependent Angiopoietin-2 Regulation in Sepsis. Critical care medicine. 2015;43(7):e230-40.
- Stiehl T, Thamm K, Kaufmann J, Schaeper U, Kirsch T, Haller H, et al. Lung-targeted RNA interference against angiopoietin-2 ameliorates multiple organ dysfunction and death in sepsis. Critical care medicine. 2014;42(10):e654-62.
- David S, Mukherjee A, Ghosh CC, Yano M, Khankin EV, Wenger JB, et al. Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis*. Critical care medicine. 2012;40(11):3034-41.
Clinical:
- Stahl K, Busch M, Fuge J, Schneider A, Manns MP, Seeliger B, et al. Therapeutic plasma exchange in acute on chronic liver failure. Journal of clinical apheresis. 2020.
- Stahl K, Schmidt BMW, Hoeper MM, Skripuletz T, Mohn N, Beutel G, et al. Extracorporeal cytokine removal in severe CAR-T cell associated cytokine release syndrome. Journal of critical care. 2020;57:124-9.
- Stahl K, Schmidt JJ, Seeliger B, Schmidt BMW, Welte T, Haller H, et al. Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock. Critical care. 2020;24(1):71.
- Seeliger B, Stahl K, Schenk H, Schmidt JJ, Wiesner O, Welte T, et al. Extracorporeal Membrane Oxygenation for Severe ARDS Due to Immune Diffuse Alveolar Hemorrhage: A Retrospective Observational Study. Chest. 2020;157(3):744-7.
- Becker LS, Stahl K, Meine TC, von Falck C, Meyer BC, Dewald CLA, et al. Non-occlusive mesenteric ischemia (NOMI): evaluation of 2D-perfusion angiography (2D-PA) for early treatment response assessment. Abdominal radiology. 2020.
- Stahl K, Seeliger B, Busch M, Wiesner O, Welte T, Eder M, et al. Maintenance Immunosuppression Is Associated With Better Outcome in the 2017/2018 Influenza Epidemic. Open forum infectious diseases. 2019;6(10):ofz381.
- Stahl K, Schenk H, Seeliger B, Wiesner O, Schmidt JJ, Bauersachs J, et al. Extracorporeal membrane oxygenation for acute respiratory distress syndrome due to Pneumocystis pneumonia. The European respiratory journal. 2019;54(3).
- Stahl K, Hadem J, Schneider A, Manns MP, Wiesner O, Schmidt BMW, et al. Therapeutic plasma exchange in acute liver failure. Journal of clinical apheresis. 2019;34(5):589-97.
- Stahl K, Busch M, Maschke SK, Schneider A, Manns MP, Fuge J, et al. A Retrospective Analysis of Nonocclusive Mesenteric Ischemia in Medical and Surgical ICU Patients: Clinical Data on Demography, Clinical Signs, and Survival. Journal of intensive care medicine. 2019:885066619837911.
- Knaup H, Stahl K, Schmidt BMW, Idowu TO, Busch M, Wiesner O, et al. Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers. Critical care. 2018;22(1):285.
Arbeitsgruppenleitung
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Prof. Dr. Dr. med Gunilla Einecke
Wissenschaftliche Mitarbeiter
- Dr. rer. nat. Florence Njau
Kooperationspartner
- PD Dr. Stephan Immenschuh, Institut für Transfusionsmedizin, MHH,
- Prof. Dr. med. Sibylle von Vietinghoff, Klinik für Nieren- und Hochdruckerkrankungen, MHH,
- Philip F. Hallon, Alberta Transplant Applied Genomics Centre, University of Alberta, Edmonton, Canada
Projektbeschreibung
Thematischer Schwerpunkt der Arbeitsgruppe sind Untersuchungen zur Transplantatdysfunktion nach Nierentransplantation. Die Ursachen der Transplantatdysfunktion sind vielfältig, und eine präzise Diagnostik ist essentiell, um eine optimale Therapie zu gewährleisten. Im klinischen Alltag unterliegt allerdings sowohl die Diagnostik als auch die Therapie dieser Patienten erheblichen Limitationen; dies sind insbesondere die folgenden: Die Diagnose beruht neben klinischen Parametern vor allem auf der histologischen Untersuchung. Diese ist als diagnostischer Goldstandard unverzichtbar, ist jedoch aufgrund der Methodik selbst in der Hand erfahrener Pathologen limitiert in ihrer Spezifität, Sensitivität und prognostischen Aussagekraft. Die histologische Untersuchung detektiert im wesentlichen die Folgen einer immunologischen Aktivität (Inflammation, Fibrose, Kreatininanstieg), nicht jedoch den zugrundeliegende Schädigungsmechanismus; eine frühe Detektion einer Schädigung oder Beurteilung der Krankheitsaktivität ist daher nur bedingt möglich. Dies wiederum erschwert deutlich die gezielte Therapie einer Transplantatdysfunktion oder die individuelle Steuerung der immunsuppressiven Erhaltungstherapie.
Wir beschäftigen uns daher mit der Untersuchung molekularer Veränderungen im Transplantat während einer Transplantatdysfunktion.
Ein wesentlicher Schwerpunkt unserer Untersuchungen liegt auf dem Krankheitsbild der humoralen Rejektion nach Nierentransplantation. Bei dieser Erkrankung kommt es durch die Entwicklung spenderspezifischer Antikörper gegen das Nierentransplantat zu einer schweren, oft chronisch verlaufenden Rejektion, die nur schwer zu therapieren ist und eine der häufigsten Ursachen für ein terminales Transplantatversagen darstellt. Der Verlauf der Erkrankung ist sehr variabel; sensitive und spezifische klinische Verlaufsparameter für die Krankheitsaktivität oder ein Monitoring der Therapie existieren nicht. Wir untersuchen daher in einem großen klinischen Kollektiv transplantierter Patienten die Krankheitsentstehung und –entwicklung hinsichtlich klinischer, histologischer und molekularer Parameter. Das langfristige Ziel dieser Untersuchungen ist eine Verbesserung der Risikostratifizierung und individuellen Therapie dieser Patienten, um damit das Langzeitüberleben der Transplantate zu verbessern.
Publikationen
Kontakt
E-Mail einecke.gunilla@mh-hannover.de
Arbeitsgruppenleitung
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Prof. Dr. Wilfried Gwinner
Wissenschaftliche Mitarbeiter
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Dr. med. Rosemarie Hanna
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Dr. med. Magret Patecki
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cand. rer. biol. hum. Dipl.-Dok. Irina Scheffner
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Dipl.-Dok. Sevda Kadah
Projektbeschreibung
Der Fokus unserer Forschung liegt in der Nieren-Transplantationsmedizin. Im Mittelpunkt steht die Untersuchung immunologischer und nicht-immunologischer Faktoren, die für Langzeit-Transplantatfunktion, Patientenüberleben und Lebensqualität wichtig sind.
Für diese Untersuchungen integrieren wir klinische Befunde mit Ergebnissen von Gewebeuntersuchungen der transplantierten Nieren und molekularen Analysen.
Zwei Ziele stehen dabei im Vordergrund: die präzise Erfassung des Ist-Zustandes des Nierentransplantates und eine möglichst genaue Voraussage der zukünftigen Langzeitentwicklung. Beide Punkte sind wichtig für die individuelle Risikobewertung und eine gut angepasste Therapie.
An unserer Forschung beteiligt sind Projektpartner der MHH (abteilungsintern; Abteilung Pathologie, Institut für Biometrie, Institut für medizinische Informatik), des Helmholtz-Zentrums für Infektionsforschung (HZI) in Braunschweig, des Zentrums für Informationsdienste und Hochleistungsrechnen (ZIH) in Dresden sowie weitere, internationale Forschungspartner.
Weitere Informationen finden Sie auf folgenden Webseiten:
https://www.eracosysmed.eu/calls/jtc-2-2017
Publikationen
Kontakt
Principal Investigator
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Prof. Dr. med. Florian P. Limbourg
Scientific Staff
- Jaba Gamrekelashvili, PhD
- Dr. rer. nat. Tamar Kapandze
- Dr. med. Susanne Fleig
- Dr. med. Khaled Dastagir
- Christian Beger
Technical Assistants
- Stefan Sablotny
Doctoral students (MD thesis)
- Cand. med. Nicolai Rohmeiß
Student Assistants/Scientific Year
- Dustin Kijas
Contact
E-Mail limbourg.florian@mh-hannover.de
Publications
Mission statement
In clinic, we see patients who suffer from hypertension and cardiovascular or renal diseases. From a clinical point of view, one major problem in these patients is vascular dysfunction and impaired regenerative capacity of blood vessels and organs, but also chronic low-grade inflammation, which promotes further dysfunction. In fact, the two seem very much interconnected. Certainly chronic inflammation triggers vascular dysfunction, however, vascular dysfunction per se seems to be a major factor triggering inflammation. This is the major focus of our current research efforts.
We were among the first to show that blood vessels influence monocyte and macrophage cell fate, which is regulated by Notch signaling, an evolutionary conserved signaling mechanisms working by direct cell-cell contact. Distinct endothelial cell populations express a Notch ligand from the Delta-like (Dll) family in specialized niches, which in turn activates Notch signaling in monocytes and controls homeostatic monocyte differentiation. The same process also promotes monocyte maturation into healing macrophages during ischemia, while conditional deletion of the ligand in endothelial cells impairs normal monocyte differentiation, which results in enhanced inflammation and impairs vessel regeneration after ischemia. This work has opened a new aspect on the concept of endothelial dysfunction and shown another important function of blood vessel independent of blood flow. However, how distinct myeloid or lymphoid cell populations respond to endothelial cells during inflammatory challenges and how their function and fate is regulated by Notch signaling is still unclear.
Announcement
DOKTORARBEIT!!!
If you are a motivated MD student not afraid of bench work and looking for a structured experimental MD thesis project, please contact us. Ideal is participation in the StrucMed program.
We are also looking for PhD students for a basic research project on regulation of monocyte and macrophage subpopulations.
Methods: advanced multicolor flow cytometry analysis and FACS sorting of cell populations, cell culture techniques, tissue and organ analysis by histology and laser scanning confocal microscopy, advanced genetic mouse models, gene expression and protein analyses.
Contact: limbourg.florian@mh-hannover.de
Current Projects
- Regulation of monocyte cell fate by blood vessels mediated by Notch signaling
Project leader: Jaba Gamrekelashvili, PhD
Monocyte and macrophage differentiation is regulated by internal programs and external cues. We were the first to demonstrate that Notch signaling is a key regulator of monocyte differentiation, which is controlled by blood vessels via endothelial expression of Notch ligands. We and others have shown that a population of monocytes, known as Ly6Clo monocytes, patrol the endothelial surface of blood vessels and mediate endothelial regeneration after arterial injury. Using cell fate tracking and advanced mouse genetics we showed that Notch regulates conversion of classical monocytes into Ly6Clo monocytes, thereby regulating monocyte cell fate under steady-state conditions. This process was controlled by a Notch ligand from the Delta-like (Dll1) family expressed by a population of endothelial cells that constitute distinct vascular niches in the bone marrow.
Flow cytometry-based t-SNE analysis of the spectrum of myeloid cell populations during vascular inflammation
Getzin T, Krishnasamy K, Gamrekelashvili J, Kapanadze T, Limbourg A, Hager C, Napp LC, Bauersachs J, Haller H, Limbourg FP. The chemokine receptor CX3CR1 coordinates monocyte recruitment and endothelial regeneration after arterial injury. EMBO Mol Med. 2018;10:151-159.
Gamrekelashvili J, Giagnorio R, Jussofie J, Soehnlein O, Duchene J, Briseno CG, Ramasamy SK, Krishnasamy K, Limbourg A, Kapanadze T, Ishifune C, Hinkel R, Radtke F, Strobl LJ, Zimber-Strobl U, Napp LC, Bauersachs J, Haller H, Yasutomo K, Kupatt C, Murphy KM, Adams RH, Weber C, Limbourg FP. Regulation of monocyte cell fate by blood vessels mediated by Notch signalling. Nature Communications. 2016;7:12597.
- Blood vessel control of macrophage maturation promotes arterial regeneration in ischemia
Project leader: Tamar Kapanadze, PhD
Ischemia causes an inflammatory response that is intended to restore perfusion and homeostasis yet often aggravates damage. We showed that recruitment of monocytes to growing collaterals involves endothelial secretion of chemoattractants, which is mediated by stretch-induced MAP kinase activation in endothelial cells. We further showed that blood vessels control macrophage differentiation and maturation from recruited monocytes via Notch signaling, which in turn promotes arteriogenesis and tissue repair. Macrophage maturation was controlled by Notch ligands expressed in vascular endothelial cells and required macrophage canonical Notch signaling via Rbpj, which simultaneously suppressed an inflammatory macrophage fate. Conversely, conditional mutant mice lacking Notch ligands or Rbpj showed accumulation of inflammatory macrophages, which antagonized arteriogenesis and tissue repair. Furthermore, the complex tissue response triggered by ischemia involves distinct vascular, metabolic and inflammatory changes. Using advanced hybrid nuclear imaging studies we showed that macrovascular and microvascular responses to ischemia are coordinated and occur during the period of macrophage infiltration, which are also the major consumers of glucose in ischemic tissue, thus contributing to a metabolic signature of ischemic tissue.
Krishnasamy K, Limbourg A, Kapanadze T, Gamrekelashvili J, Beger C, Häger C, Lozanovski VJ, Falk CS, Napp LC, Bauersachs J, Mack M, Haller H, Weber C, Adams RH, Limbourg FP. Blood vessel control of macrophage maturation promotes arteriogenesis in ischemia. Nature communications. 2017;8:952.
Kapanadze T, Bankstahl JP, Wittneben A, Koestner W, Ballmaier M, Gamrekelashvili J, Krishnasamy K, Limbourg A, Ross TL, Meyer GJ, Haller H, Bengel FM, Limbourg FP. Multimodal and Multiscale Analysis Reveals Distinct Vascular, Metabolic and Inflammatory Components of the Tissue Response to Limb Ischemia. Theranostics. 2019;9:152-166.
Limbourg A, von Felden J, Jagavelu K, Krishnasamy K, Napp LC, Kapopara PR, Gaestel M, Schieffer B, Bauersachs J, Limbourg FP, Bavendiek U. MAP-Kinase Activated Protein Kinase 2 Links Endothelial Activation and Monocyte/macrophage Recruitment in Arteriogenesis. PLoS One. 2015;10:e0138542.
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Cross-talk of blood vessels and immune cells in kidney inflammation: formation and function of tertiary lymphatic structures
Project leader: Dr. med. Susanne Fleig
Tertiary lymphatic structures (TLS) form in response to chronic inflammation in non-lymphoid organs such as the kidney to support the immune response. As such, they occur in chronic infection or transplantation, but also due to autoimmunity or cancer. They resemble a lymph node in cell content and architecture (although lacking a capsule), and they are typically located in close proximity to blood and lymph vessels. Depending on their specific function (development of immune tolerance or production of autoantibodies, e.g.), they may be helpful or deleterious. TLS can become large structures and inhibit kidney function also by local infiltration; in fact, the anti-B-cell antibody Rituximab is now standard of care for many autoimmune diseases of the kidney, such as ANCA Nephritis or membranous nephritis.
Tertiary lymphatic structures development is enigmatic. While many groups focus on the immune cells or the local stromal cells as starting point for TLS, in the current project we want to understand the role of the vasculature in attracting immune cells and in orchestrating formation of TLS. More generally, we are interested in how different vascular beds of the kidney form and how the interact with and influence immune cells.
High-resolution confocal image of glomerolum and surrounding tissue.
DOKTORARBEIT!!! If you are a motivated MD student not afraid of bench work and looking for a structured experimental MD thesis project, please contact us. Methods: kidney section and whole mount staining, confocal microscopy, multicolor staining flow cytometry and FACS sorting of cell populations as well as general transcription and protein analyses.
Contact: fleig.susanne@mh-hannover.de
- Clinical hypertension research
Project leader: Christian Beger
Hypertension is the most important risk factor for chronic disease and premature death. Despite improved awareness and effective therapeutic strategies, uncontrolled or treatment-resistant hypertension remains a major problem. To better understand causes and mechanisms of resistant hypertension, and in order to develop new diagnostic and therapeutic strategies, we established the clinical and biomaterial database PRIORITY (prospective cohort: resistant hypertension). We are particularly interested in special forms of hypertension associated with a low renin phenotype, since many of these patients suffer from an endocrine form of hypertension due to inadequate aldosteron production (primary aldosteronism), which affects 5% of hypertension patients. Furthermore, we try to establish and evaluate new strategies to control and improve medication-adherence.
Beger, C., H. Haller, and F.P. Limbourg. 2019. [Two case reports on resistant hypertension]. Der Internist 60:529-532.
Fleig, S.V., B. Weger, H. Haller, and F.P. Limbourg. 2018. Effectiveness of a Fixed-Dose, Single-Pill Combination of Perindopril and Amlodipine in Patients with Hypertension: A Non-Interventional Study. Advances in therapy 35:353-366.
Koziolek, M., J. Beige, M. Wallbach, D. Zenker, G. Henning, M. Halbach, N. Mader, F. Mahfoud, G. Schlieper, V. Schwenger, M. Hausberg, J. Borgel, M. Lodde, M. van der Giet, J. Muller-Ehmsen, J. Passauer, S. Parmentier, S. Luders, B.K. Kramer, S. Buttner, F. Limbourg, J. Jordan, O. Vonend, H.G. Predel, and H. Reuter. 2017. [Baroreceptor activation therapy for therapy-resistant hypertension: indications and patient selection : Recommendations of the BAT consensus group 2017]. Der Internist 58:1114-1123.
- Regulation of inflammation and vascular regeneration in reconstructive wound healing
Project leader: Dr. med. Khaled Dastagir
Large tissue defects are a major problem in reconstructive or plastic surgery, and the ensuing wound healing defects put patients at risk for amputation or sepsis. Wound healing and tissue perfusion depends on angiogenesis and arteriogenesis (vascular collateralization), which is influence by the nature of the inflammatory response. Identification of the key regulators of inflammation and angiogenesis in the skin could result in new therapy strategies for large wounds. We aim to investigate the molecular regulation of inflammatory cell differentiation by Notch signaling, and the resultant impact on blood vessel regeneration and tissue healing, using a newly developed surgical wound model.
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Regulation of developmental angiogenesis and postnatal arteriogenesis by Notch signaling
Vascular development requires arterio-venous differentiation and vascular remodeling, which is mediated by Notch signaling. During angiogenesis, single endothelial cells (EC) specialize into tip cells that guide vessel sprouting towards growth factor gradients and instruct the adjacent vessel stalk. The balance between tip and stalk cells is regulated by endothelial Notch signaling through the expression of Notch ligand Delta- like 4 (Dll4) in tip cells, which suppresses a tip cell fate in adjacent stalk cells. We have shown that myeloid cells regulate tip cell numbers and Dll4 expression via the Notch ligand Dll1 during vascular development in the retina, which influences angiogenesis and vascular branching morphogenesis. Furthermore, we have also shown that Notch signaling in endothelial cells is crucial for normal embryonic development and blood vessel maturation, since conditional endothelial deletion of Notch1 resulted in impaired remodeling of the embryonic vasculature. We went on to establish an important role for Notch signaling in postnatal arteriogenesis, which is required to restore perfusion to ischemic organs. In a state-of-the-art mouse model of hind limb ischemia developed by us, expression of the Dll ligand was strongly induced in ischemic collateral blood vessels, leading to activation of Notch signaling and collateral growth. In loss-of-function mutant mice, endothelial Notch activation and arterial collateral growth were abrogated and recovery of blood flow was severely impaired.
Haupt F, Krishnasamy K, Napp LC, Augustynik M, Limbourg A, Gamrekelashvili J, Bauersachs J, Haller H, Limbourg FP. Retinal myeloid cells regulate tip cell selection and vascular branching morphogenesis via Notch ligand Delta-like 1. Sci Rep. 2019;9:9798.
Limbourg FP, Takeshita K, Radtke F, Bronson RT, Chin MT, Liao JK. Essential role of endothelial Notch1 in angiogenesis. Circulation. 2005;111:1826-1832.
Limbourg A, Korff T, Napp LC, Schaper W, Drexler H, Limbourg FP. Evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb ischemia. Nat Protoc. 2009;4:1737-1746.
Limbourg A, Ploom M, Elligsen D, Sorensen I, Ziegelhoeffer T, Gossler A, Drexler H, Limbourg FP. Notch ligand Delta-like 1 is essential for postnatal arteriogenesis. Circ Res. 2007;100:363-371.
Recent Research Funding
2019-2021
Mhh/ Deutsche Forschungsgemeinschaft: PRACTIS
Dr. med. Khaled Dastagir (Limbourg lab)
2019-2020
Mhh intern: HiLF II
Dr. med. Susanne Fleig (Limbourg lab)
2018-2021
Sponsor: Deutsche Forschungsgemeinschaft
PI: Limbourg Li948/7-1
Topographie der vaskulären Nische bei Ischämie
2017-2020
Sponsor: Deutsche Forschungsgemeinschaft
PI: Gamrekelashvili Ga2443/2-1 (Limbourg lab)
Regulation of monocyte cell fate by blood vessels through Notch signaling and significance for vascular repair
2017-2019
Sponsor: Junge Akademie / Clinical Scientist Programm (MHH/DFG)
Dr. med. Susanne Fleig (Limbourg lab)
2015-2016
Sponsor: Deutsche Stiftung für Herzforschung
PI: Gamrekelashvili/Limbourg
Patrolling monocytes in endothelial function and molecular regulation
2016-2018
Sponsor: Else-Kröner-Foundation for Kidney Research
PI: Kapanadze/Limbourg
Macrophage cell fate in ischemic kidney injury
2016-2017
Sponsor: Deutsche Stiftung für Herzforschung
PI: Gamrekelashvili/Limbourg
Patrolling monocytes in endothelial regeneration – function and molecular regulation
2014-2016
Sponsor: Integrated Research and Treatment Center for Transplantation/ Bundesministerium für Bildung und Foschung
PI: Limbourg IFB-Tx CBT_8
Autologous macrophage transplantation for kidney repair in patients with atherosclerotic renovascular disease and hypertension (AMTraK)
2014-2016
Sponsor: Deutsche Forschungsgemeinschaft
PI: Limbourg Li948/5-1
Myeloische Zelldifferenzierung in der ischämischen Neovaskularisierung
Arbeitsgruppenleitung
- Prof. Dr. med. Roland Schmitt
Wissenschaftliche Mitarbeiter
- Dr. rer. nat. Inga Sörensen-Zender
- Dr. med. Vera Wulfmeyer
- Chieh Ming Liao
- Dr. rer. nat. Payel Sen, M.D.
- Dr. med. Thomas Krämer
Technische Assistenten
- Britta Gewecke
Projektbeschreibung
Als Antwort auf einen zellulären Tubulusschaden wie er beim akuten Nierenversagen vorkommt, reagiert die Niere normalerweise mit einer gut koordinierten Sequenz epithelialer Reparatur- und Regenerationsprozesse, die zur Wiederherstellung der Organstruktur und –funktion führen sollen. Unter bestimmten Umständen, z.B. im Alter, sind diese Vorgänge fehlerhaft oder ungenügend, so dass der Schaden bestehen bleibt, oder es zur Organfibrosierung kommt. Unser Schwerpunkt ist die Erforschung neuer Pathomechanismen, die dieser fehlerhaften Regeneration zu Grunde liegen. Dabei konzentrieren wir uns auf renale Kandidatenmoleküle und Signalwege, die alters-abhängig reguliert sind. Letztlich sollen unsere Untersuchungen eine Basis schaffen, auf der neue therapeutische Strategien entwickelt werden können, die das Reparatur- und Regenerationspotential alter, bzw. bereits vorgeschädigter Nieren verbessern.
Publikationen
Kontakt
E-Mail schmitt.roland@mh-hannover.de
Prinipal Investigator
- Prof. Dr. med. Sibylle von Vietinghoff
Members
- Julia Volkmann, MD
- Anne Hüsing
- Janis Casper, MD student
- Eva Roy-Chowdhury, MD student
- Nicolas Brauns, MD student
- Martina Flechsig, MTA
- Tamara Tuchel, BTA
Research interest
We are interested in the role and regulation of leukocytes in vascular inflammation in renal failure.
Chronic kidney disease affects a large proportion of the population. It impairs host response to pathogens but also increases atherosclerotic inflammation and mortality. Chronic inflammation of the arterial wall is a major contributor to atherosclerotic plaque growth and instability.
We investigate innate immune cells and the vascular inflammatory infiltrate in patients with chronic kidney disease and mouse models of atherosclerosis. A focus of our work has been the role of the T cell cytokine Interleukin 17 in regulation of innate immune cells (Ge et al., 2013, Dong et al, 2016, Nordlohne et al., 2018).
Innate leukocytes, especially neutrophilic granulocytes and monocytes and macrophages in uremia are studied also in other conditions.
For example, we have investigated kidney macrophages after transplantation and correlated their abundance with transplant survival and complications such as urinary tract infections.
Peritoneal dialysis is an important mode of renal replacement therapy. It can be a successful for years or fail due to peritoneal membrane thickening and inflammatory changes. We use our immunologic interest to better understand macrophages crosstalk with the peritoneal membrane.
In summary, we aim to improve mechanistic understanding of innate inflammation in renal impairment with the goal to define specific treatment avenues.
Support
Our work is supported by Deutsche Forschungsgemeinschaft, Else Kröner Fresenius Stiftung, IfBtx and others
Publications
Contact
Arbeitsgruppenleitung
- Prof. Dr. Annette D. Wagner
Projektbeschreibung
Forschungsschwerpunkt ist die Untersuchung der Möglichkeiten der Digitalisierung in der Medizin - insbesondere den möglichen Einsatz künstlicher Intelligenz bei der Diagnose seltener Erkrankungen. In einem Projekt mit Ada Health haben wir ein digitales Diagnose-Assistenzsystem für seltene Erkrankungen evaluiert. Ziel des Systems ist es, Ärzte dabei zu unterstützen, komplexe und seltene Erkrankungen korrekt und rechtzeitig zu erkennen, um eine zielführende Überweisung der Patienten an Zentren für seltene Erkrankungen zu ermöglichen und zeitnah eine adäquate Therapie einzuleiten. Durch eine verbesserte Zuweisungsqualität als Effekt solcher Systeme können Kostensenkungen im Gesundheitssystem erreicht werden. Aufbauend auf diesen Ergebnissen ist eine Fortführung des Projektes unter Einbeziehung weiterer interner und externer Forschungseinrichtungen geplant.
Aufbauend auf den Ergebnissen der bereits publizierten retrospektiven Studie sollen zukünftig verschiedene Subgruppen seltener Erkrankungen prospektiv untersucht werden. Ziel der Untersuchung ist es auch, die deskriptive Untersuchung der Genauigkeit eines Self-Assessment Systems im Rahmen einer App für spezifische Gruppen seltener Erkrankungen zu prüfen. Ein weiterer Schwerpunkt ist die Optimierung der Self-Assessment Technologie für die Erkennung eines breiten Spektrums seltener Erkrankungen. Bei erfolgreicher Umsetzung sind signifikante Effekte auf die Möglichkeit der Identifizierung Betroffener und damit auf deren Zeit bis zur Diagnose zu erhoffen. Ein entscheidender primärer Endpunkt dieser prospektiven Studie ist die Übereinstimmung der von der App vorgeschlagenen Erkrankung im Vergleich mit der bestätigten Diagnose der(s) Patientin(en).
Im Rahmen der Entwicklung neuer Lehrkonzepte ist die Vermittlung digitaler Kompetenzen geplant. Ziel ist es, dass die Lehrformate über das konkrete Gebiet hinaus grundlegende und nachhaltig wirkende digitale Kompetenzen vermittelt, die das lebenslange Lernen und den Arzt-Patienten-Dialog auf eine neue Basis stellen. Damit soll das Projekt Impulse für das Medizinstudium und das Arzt-Patientenverhältnis der Zukunft setzen. Die Studierenden sollen Diagnoseunterstützungssysteme im Rahmen eines interaktiven Seminars sowie am Krankenbett selbständig anwenden. Die Möglichkeiten und Limitationen der Systeme sollen in verschiedenen Szenarien kritisch untersucht werden. Die grundlegenden relevanten Aspekte künstlicher Intelligenz sollen erläutert werden, um daraus ableitbare Potentiale der Systeme zu vermitteln.
Durch die genaue klinische Phänotypisierung konnten verschiedene Patientengruppen mit seltenen Systemerkrankungen gebündelt werden. Bei diesen Subgruppen handelt es sich meist um Erkrankungen, deren genetische Grundlage noch nicht bekannt ist. Aus diesem Grunde sollen zukünftig Patientengruppen mit einer aussagekräftigen Fallzahl auf gemeinsame genetische Veränderungen hin untersucht werden. Die genaue Phänotypisierung der Patienten und die Sammlung des Probenmaterials sollen die Etablierung einer Biobankstruktur und Vernetzung mit den spezifischen Unterzentren fördern.