Overview of research projects

    Below, you will find an overview of all offered research projects. By clicking on the links, you can navigate to the pages of the particular groups.

     

    Prof. Stephan Baldus / Dr. Anna Klinke

    Project summary:

    Myeloperoxidase-mediated modulation of glycocalyx integrity and its impact on vascular dysfunction

    Vascular inflammatory processes are critically linked with the pathogenesis of various cardiovascular diseases. Impairment of vascular integrity implies disturbance of the endothelial glycocalyx, which represents a gel-like structure lining the blood vessels. It is mainly comprised of protein-bound glucosaminoglycans and serves as a critical regulator of vascular function influencing endothelial permeability, blood flow velocity, shear-mediated production of nitric oxide and leukocyte extravasation. Due to electrostatic interactions the highly cationic heme enzyme myeloperoxidase (MPO), which is abundantly expressed and released by polymorphonuclear neutrophils (PMN), avidly binds to the endothelial glycocalyx. MPO exerts potent pro-oxidant and pro-inflammatory properties and has been identified as a mediator of endothelial dysfunction and atherosclerosis. It has been shown recently, that MPO binding to the glycocalyx decreases the electrostatic repulsion between the endothelium and the leukocyte’s surface thereby inducing leukocyte recruitment, which represents a critical inflammatory event.

    The current project aims to further characterize MPO’s impact on the endothelial glycocalyx and the consequences of the interaction on vascular integrity. Cell culture and in-vivo techniques using wild-type and MPO-deficient mice will be employed. Glycocalyx charge and structure upon MPO exposure will be determined by histological and immunofluorescence staining and by electron microscopy. Endothelial permeability, microhemorheology and mechanotransduction will be investigated in cultured cells under flow conditions and in mice using intravital microscopy of postcapillary venules of the cremaster muscle.

    PhD student: Kashish Manchada
    Kashish Manchada received the Bachelor of Science degree in Biochemistry in his native New Delhi from University of Delhi in 2011. He completed the Master’s degree in Molecular Biotechnology from the University of Bonn, Germany, in 2013 before he applied for the CCRC Graduate Program at the end of 2013 and has been awarded a CCRC PhD felloewship. Since May 2014, he is performing his PhD in the research group of and under the supervision of Prof. Dr. Stephan Baldus and Dr. Anna Klinke (Dept. III of Internal Medicine).

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    Prof. Thomas Benzing

    Project description

    Glomerular disease represents a major cause of chronic kidney disease affecting more than 5% of all human beings world-wide. These disorders share common features such as proteinuria and the loss of renal function due to progressive damage of the glomerular microcirculation. Inflammation conveys the development of glomerular injury and is a major cause of  progressive kidney disease. We have inhibited NF-κB signaling in podocytes, the pericyte-like visceral epithelial cells of the glomerular capillaries, by specific ablation of the NF-κB essential modulator (NEMO, IKKγ). Podocyte-restricted NF-kB inhibition was highly protective in experimental models of glomerular injury. Mice with podocyte-restricted NEMO ablation recovered much faster after damage, showed rapid remission of proteinuria and displayed robust restoration of the glomerular microcirculation suggesting that proinflammatory signaling in podocytes, the pericytes of the glomerular microcirculation, is essential for progressive injury. Thus, the aim of this project is to further define the mechanisms how inflammatory signaling in podocytes contributes to progressive damage of the glomerular microcirculation. We will specifically study the underlying mechanisms of injury that are amenable to develop therapeutic interventions to develop novel treatments of progressive glomerular disease.

    PhD Student: Manaswita Jain
    Manaswita Jain was born in New Delhi, India, and received the Bachelor’s degree in Biotechnology from the Amity University in Noida, India, in 2010. After that she accomplished a Master's degree Biological Sciences (Cell Biology) at the University of Cologne, Germany, in 2013. Afterwards, Manaswita Jain has been awarded a fellowship to participate in the CCRC Graduate Program Since May 2014 she is performing her PhD in the research group of and under the supervision of Prof. Dr. Thomas Benzing (Dept. II of Internal Medicine).

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    Prof. Jens Brüning

    Project description

    Role of Interleukin (6)-Signaling in Obesity-Associated Atherosclerosis

    Obesity represents a major risk factor not only for the development of type 2 diabetes mellitus, but also for atherosclerosis. More recently, increased weight gain has been associated with a state of chronic pro-inflammatory tone due to lymphocyte and macrophage infiltration into white adipose tissue (WAT) and subsequent release of inflammatory cytokines such as TNF and IL-6. While TNF has been characterized as a critical regulator of glucose homeostasis and atherosclerosis in this setting, the role of Il-6 in the development of obesity-associated atherosclerosis remains ill defined. We have recently defined critical roles for IL-6 in the regulation of T-lymphocyte function as well as macrophage polarization with respect to the manifestation of innate and adaptive immune responses. Thus, the aim of the current proposal is to define the role of T-cell- and macrophage-intrinsic IL-6-signalling in the development of obesity-associated metabolic disorders and atherosclerosis.

    PhD Student: Philipp Hammerschmidt
    Philipp Hammerschmidt was born in Tuebingen, Germany, and received the Bachelor’s degree in Biology from the University of Cologne in 2013. Afterwards, he started the “Fast Track” Master program at the Graduate School for Biological Sciences of the University of Cologne and will soon receive the Master’s degree in Genetics and Cell Biology. Philipp Hammerschmidt has been awarded a PhD fellowship to participate in the CCRC Graduate Program and will perform his PhD in the research group of and under the supervision of Prof. Dr. Jens Brüning (MPI of Neurological Research).

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    Prof. Manolis Pasparakis

    Project description

    Atherosclerosis is a progressive disease characterized by the formation of plaques in the sub endothelial space of the large arteries. Atherosclerosis represents the main risk factor for cardiovascular disease and is the leading cause of death in developed countries. Atherosclerosis has been linked to hypercholesterolemia for decades, however in the last years atherosclerosis has been recognized as a chronic inflammatory disease. The development and growth of an atherosclerotic plaque is the result of a chronic non-resolving inflammatory response involving the recruitment and entrapment of monocytes in the subendothelial space, where they mature into macrophages that take up lipids becoming foam cells. The death of lipid-laden macrophages is believed to critically affect the progression of atherosclerosis. In early lesions, apoptotic foam cells are phagocytosed by efferocytes resulting in plaque regression. In advanced lesions inefficient efferocytosis results in the accumulation of dead foam cells that release proinflammatory factors and form a necrotic core within the plaque. The mechanisms regulating macrophage death in atherosclerotic plaques remain poorly understood. The aim of this project is to experimentally address the mechanisms inducing macrophage death in atherosclerotic plaques and their role in the development and progression of atherosclerosis.

    PhD Student: Antonis Chatzigiagkos
    Antonis Chatzigiagkos was born in Kozani, Greece. In 2007, he started his studies at the Faculty of Veterinary Medicine at the Aristotle University of Thessaloniki and received the Degree in Veterinary Medicine in 2013. Upon completion of his studies he worked in the Pathology research laboratory of the School of Veterinary Medicine, on projects in collaboration with the DCM of MIT. He applied for the Graduate Program of the Cologne Cardiovascular Research Center (CCRC) and has been awarded a Ph.D. fellowship. Since August 2014, he is performing his Ph.D. dissertation in the research group of and under the supervision of Prof. Manolis Pasparakis (CECAD Cologne).

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    Prof. Stephan Rosenkranz / Dr. Henrik ten Freyhaus

    Project description:

    Role of the 6-transmembrane protein Stamp2 in Pulmonary Hypertension

    A chronic, low-grade inflammation at key metabolic organs, including adipose tissue, is a hallmark of obesity and contributes to related complications such as insulin resistance. Importantly, both nutrients (such as glucose and lipids) and cytokines are able to activate inflammatory and stress signaling pathways such as JNK and IKK. The impact of nutrients on inflammatory pathways demands the existence of counterregulatory mechanisms to prevent overt inflammation upon physiological fluctuations in nutrient availability. Recently, the six-transmembrane protein of prostate (Stamp)-2 was discovered as a molecule involved in such a role in adipose tissue. Stamp2 expression was regulated by fasting/feeding in mice and Stamp2-deficient mice developed metabolic syndrome and showed macrophage infiltration of visceral adipose tissue. We recently discovered an important role of Stamp2 in macrophages. In these cells, Stamp2 serves as an anti-inflammatory mediator by regulating NADP/NADPH homeostasis. Furthermore, Stamp2-deficiency promotes early atherosclerosis and inflammation within atherosclerotic plaques in mice. Consequently, Stamp2 appears to be an important anti-inflammatory protein in various pathologies. Pulmonary hypertension (PH) is associated with a poor prognosis. Inflammatory processes are critical during initiation and progression of the disease. Thus, the aim of the current proposal is to define the role of Stamp2 in the control of inflammation in the pulmonary vasculature and in PH.

    PhD Student: Mehreen Batool
    Mehreen Batool was born in Islamabad, Pakistan and received the Bachelor’s degree in Organic Chemistry from the University of the Punjab, Pakistan, in 2009. Two years later, she earned the Master’s degree in Biotechnology from the COMSATS Institute of Information Technology in Abbottabad, Pakistan. For deepening her studies she went to Sweden in 2012 an earned a Master’s degree of Molecular Biology from the University of Skövde in 2013. For intensifying her biomedical skills she applied for the CCRC Graduate Program and has been awarded a Ph.D. fellowship. Since March 2014, she is performing her PhD dissertation in the research group of and under the supervision of Prof. Dr. Stephan Rosenkranz (Dept. III of Internal Medicine).

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    Prof. Björn Schumacher

    Project description:

    Innate immune responses to DNA damage in ageing and disease

    DNA damage accumulation is thought to causally contribute to the functional decline in aging (Schumacher et al, 2008a). Cellular DNA damage responses (DDR) evoke cell cycle arrest, apoptosis, and cellular senescence that are essential for tumour suppression (Reinhardt & Schumacher, 2012). It has been suggested that inflammatory responses to DNA damage accumulation comprise a causal factor for tissue degeneration with aging. We aim to gain insight into how the innate immune system mediates systemic responses to DNA damage accumulation with aging. Understanding the mechanistic links between DNA damage and innate immune responses might reveal new therapeutic strategies to counteract chronic inflammation in aging-associated disease.

    We aim to determine the mechanisms through which the innate immune response is mediated upon DNA damage. To achieve this we will employ the powerful experimental system of C. elegans and use the synergisms of the CCRC to explore functional conservation of innate immune responses to DNA damage and assess their role in vascular remodeling.

    PhD Student: Najmeh Soltanmohammadi
    Najmeh Soltanmohammadi was born in Isfahan, Iran, and received the Bachelor’s degree in Biology from the University of Payam Noor in Tehran, Iran, in 2010. Afterwards, she accomplished a Master's degree in Biological Sciences at the University of Cologne and finished in 2013. She has been awarded a PhD fellowship to participate in the CCRC Graduate Program and is since Jan. 2014 performing her PhD in the research group of and under the supervision of Prof. Björn Schumacher (CECAD Cologne).

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    Dr. Aleksandra Trifunovic / Dr. Volker Rudolph

    Project description:

    The role of mitochondrial respiratory chain and oxidative phosphorylation (OXPHOS) in vascular system

    Aims: Mitochondrial dysfunction is part of both normal and premature ageing, and can contribute to inflammation, cell senescence and apoptosis. Increasing evidence indicates that mitochondrial damage and dysfunction also occur in vascular diseases, in particular atherosclerosis, and may contribute to the multiple pathological processes underlying the disease. The vascular endothelium or smooth muscle cells (VSMC) are relatively independent of mitochondrial energy generating oxidative pathways, therefore mitochondria function in these cells have been somewhat neglected. Nevertheless, both cell types have an extensive mitochondrial network, suggesting that mitochondrial function may be important in response to stress and signalling in these cells. Using mouse models, in which mitochondrial protein synthesis and hence oxidative phosphorylation is dirupted in endothelial and vascular smooth muscle, respectively, this project plans to shed more light on the role of mitochondrial function in these two cell types and critically evaluate the role of mitochondrial function in vascular disease.

    PhD Student: Stephan Lotter
    Stephan Lotter received the Bachelor of Science degree in Biology in his native Cologne, Germany in 2011. During his studies he was holder of a scholarship of the ERASMUS program and went to Odense, Denmark, for joining a research project. In 2011, he started the Master's degree in Biological Sciences at the University of Cologne and will soon be finished. He applied for the CCRC Graduate Program and since Feb. 2014, he is performing his PhD in the group of Prof. Dr. Aleksandra Trifunovic and Dr. Volker Rudolph (CECAD Cologne).

     

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    Prof. Thorsten Wahlers / Dr. Yeong-Hoon Choi

    Project description:

    The heterodimeric hypoxia inducible transcription factors (HIF) are the key regulators of the pro-angiogeneic response to hypoxia. However, not only hypoxia, also pro-inflammatory signaling (i.e. tumor necrosis factor-α (TNF-α) and nuclear factor-ĸB (NF-ĸB) activation) can directly induce the pro-angiogeneic HIF signaling pathway.

    Pressure overload left ventricular hypertrophy (LVH) results - if untreated – in progressive heat failure. While hypoxia as well as inflammation markers are elevated in LVH, the hypertrophic myocardium fails to respond to the pro-angiogeneic signaling, resulting in progressive heart failure. The aim of the presented proposal is investigate whether the increased expression of TNF-α in LV hypertrophy results in differential expression of the hypoxia inducible factors-1 and -2 and, thereby, preventing the adaptive angiogenesis. If this is the case, strategies will be developed to disrupt this cascade by manipulating the inflammatory environment, in order to preserve the relationship between contractile mass and blood supply, possibly delaying the onset of LV dilation and heart failure.

    PhD Student: Mostafa Somak
    Mostafa Somak received the Bachelor’s degree in Pharmaceutical Sciences and Clinical Pharmacy at the Helwan University in his native Cairo, Egypt, in 2010. He completed the Master’s degree in Molecular Medicine from the University of Göttingen, Germany, in 2013. Afterwards, he has been awarded a Ph.D. fellowship to participate in the Graduate Program of the Cologne Cardiovascular Research Center (CCRC) and is now performing her PhD dissertation in the research group of and under the supervision of Prof. Dr. Thorsten Wahlers and Dr. Choi (Dept. III of Internal Medicine).

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