Excellence Cluster - Cardio-Pulmonary System

Project areas – contribution of ECCPS scientists

Within the broad field of the cardio-pulmonary system, the ECCPS faculty has defined nine Project Areas which encompass the most promising topics and/or the areas of most need for novel approaches at the forefront of heart and lung research. The exploration of these cutting edge agendas has been organized into a hierarchical structure, as the ECCPS aims to address all of the Project Areas on predefined levels that span from molecular signatures and the identification of novel molecular targets to the instigation of clinical trials.
From the short summaries provided, it is obvious, that the horizon and scope of these cooperative projects will be further enlarged by the integration of the planned new chairs and research groups funded by the ECCPS budget together with additional extramural funding. The cooperative projects in their current state however demonstrate that the ECCPS faculty is already capable of addressing the different agendas at the required levels of complexity, and that the ECCPS faculty has already commenced to work on a cooperative basis, combining scientists from different institutions in most of the projects.

Project Area A Stem/progenitor cells in development, repair and therapy

Prof. Dr. Braun, Thomas / Prof. Dr. Dimmeler, Stefanie

A growing number of studies have reported the isolation of putative cardiac and vascular progenitor cells from a variety of tissue sources and examined their effects on promoting the repair of the injured heart as well as their impact on the cardiovascular system. Since stem cells have yet to acquire the identity of any specific cell type, are still not committed to any dedicated function, and can renew themselves, they might not only be used as tools to study tissue formation but might also be employed for tissue repair and regeneration. However, little is known about the mechanisms, by which progenitor cells improve cardiac and vascular function. There is currently considerable controversial discussion about the contributions of differentiation, cellular fusion and/or paracrine effects. With regard to the lung, endogenous progenitor cells have been identified in both the proximal and the distal lung, however, there is limited data regarding their lineage relationships, self-renewal properties, clonality and repopulation from bone marrow derived precursors. Given the concerns about the ability of adult stem cells to rebuild diseased heart and lung tissue cell-autonomously, it seems overdue to identify and dissect those signals that direct the migration, renewal and differentiation of distinct adult and embryonic stem/progenitor cell populations. The functional benefits of the autologous transplantation of bone marrow derived progenitor cells for a treatment of ischemic heart disease should be exploited, improved, and mechanistically underpinned, and its impact on lung vascular and lung parenchymal remodeling be analyzed. The improved knowledge of the molecules and processes that govern the differentiation and renewal of progenitor cells during development and disease will result in a further refinement of already explored therapies and provide a rationale for new clinical treatments.

Scientific focus

The goals of this project area are: (i) to identify stem cell populations that might mediate cardiac regeneration and neovascularization and take part in lung vascular and parenchymal remodeling and repair processes; (ii) to decipher the developmental pathways that lead to the formation of stem cell niches; (iii) to disclose signals that lead to activation of endogenous repair mechanisms including signals that might emanate from circulating blood borne progenitor cells; (iv) to generate progenitor cells from various sources including embryonic and adult stem cells for therapeutic interventions; (v) to improve existing therapeutic approaches to cardiovascular diseases by accelerating mechanisms that lead to a better homing of cells that are of therapeutic value, and to extend these approaches to pulmonary diseases; (vi) in the long run, to genetically manipulate progenitor cells for targeted therapy in heart and lung disease. The project area will employ state-of-the-art genetic and biochemical approaches, animal models and imaging techniques for visualizing, identifying and tracking cells. Planned/ongoing clinical trials will be incorporated into the project area and will directly benefit from ongoing laboratory findings. Given the challenging perspectives and the clinical importance of this project area, the ECCPS plans to install a professorship in “Stem Cell Fate and Differentiation” to further complement the expertise of the initial participants. Moreover, this research area will be further supported by the Max-Planck chair for Vascular Development and Patterning, planned to be installed in the next future.

Cooperative projects planned by the current ECCPS faculty
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Project Area B Vascular remodeling, anti-remodeling and reverse-remodeling

Prof. Dr. Grimminger, Friedrich / Prof. Dr. Zeiher, Andreas M

The term remodeling describes changes in the structure of blood vessels. In its maladaptive form of inward remodeling it is responsible for loss of vessel patency in the leading abnormalities of the heart and lung vasculature, coronary artery disease and pulmonary artery hypertension. Moreover, allograft vasculopathy after heart transplantation represents a rapidly progressive variant of pathological remodeling. The pathophysiological processes underlying vascular remodeling in the pulmonary and coronary circulation share a variety of common mechanisms, such as inflammation and smooth muscle cell proliferation/differentiation/migration, but display also marked differences such as responsiveness to hypoxia. Deciphering the different mechanisms involved in these processes will facilitate the development of novel organ- and disease-specific tailored therapies. Recent findings of the ECCPS faculty in preclinical and clinical studies indicate that the progressive vascular remodeling in pulmonary hypertension may not only be stopped (“anti-remodeling”), but reversed (“reverse-remodeling”), this is a paradigm shift away from that of the era of so-called “fixed” structural changes. We have to declare the restoration of physiological vascular structure as a main therapeutic goal. The projects in this area, spanning from the identification of new molecular targets to clinical studies, will pursue this goal for the sake of novel therapies, both in the “prototype” disease, pulmonary arterial hypertension and the cardiac vascular abnormalities, coronary artery disease and allograft vasculopathy.

Scientific focus

The aim of this project area is to define molecular signatures of pathological vascular remodeling and to develop therapeutic strategies for tailored anti- and reverse remodeling, to be tested both in preclinical and clinical studies. The focus will lie on i) inflammatory processes as initiators and accelerators of remodeling (e.g. monocyte/macrophage-released cytochrome P450 products, reactive nitrogen species) and anti-inflammatory concepts (e.g. regulatory T cells, immunomodulation), ii) modulators of smooth muscle cell function and growth, with particular emphasis on the TGF-β/BMP system (e.g. analysis of Smad phosphorylation, sumoylation, DNA binding and downstream gene regulation) and epigenetic regulation of smooth muscle cell differentiation (e.g. by using HDAC inhibitors for prevention of restenosis), and iii) novel circulating, blood-derived mediators leading to plaque destabilization, like PlGF. Recent findings concerning anti/reverse-remodeling properties of phosphodiesterase inhibitors, guanylylate cyclase activators and guanylylate cyclase stimulators will be refined in preclinical studies and translated into proof-of-concept and larger scale clinical trials. Moreover, with the use of tyrosine kinase inhibitors (e.g. inhibitor of platelet derived growth factor) and aerosolized nanoparticle-based gene delivery for pulmonary hypertension as well as targeting the p38 pathway and scavenging PlGF by its soluble receptor sFlt-1 for coronary artery disease, completely new fields of intervention will be opened. The activities in this project area will be further supported by the Max-Planck chairs for Vascular Development and Patterning and Vascular Signaling and Remodeling as well as the endowed Chair for Pulmonary Hypertension, planed to be installed in the near future.

Cooperative projects planned by the current ECCPS faculty
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Project Area C Angiogenesis and regeneration

Prof. Dr. Plate, Karl-Heinz / Dr. Voswinckel, Robert

Angiogenesis is a key feature in embryogenesis and postnatal vascular and tissue growth, both physiological and pathological. The central role of angiogenesis and vascular integrity in relevant cardiovascular diseases like atherosclerosis and myocardial ischemia is self-evident; loss of microvessels has direct impact on cardiac muscle function and survival. In the lung, microvascular integrity is critically important for ensuring gas exchange and maintenance of the delicate architecture of the alveolar compartment. Understanding the complex molecular and cellular interplay involved in heart and lung macro- and microvascular homeostasis should lead to the identification of new targets for potential therapy with the aim of maintaining physiological vascular supply. Moreover, the stimulation and direction of angiogenesis is an indispensable prerequisite for each regenerative approach focusing on restoring damaged tissue. Regeneration strategies will profit from understanding the principles of developmental biology, as one aim is to re-activate (while spatially and temporally controlling) genetically inherent programs of morphogenesis and regeneration within organotypic tissue. Obviously such an endeavor is essential to open entirely new avenues for the treatment of cardiac insufficiency due to maladaptive hypertrophy and ischemic loss of cardiomyocytes, and for treatment of hitherto fully unresolved lung diseases with loss of integer alveolar architecture such as emphysema and lung fibrosis.

Scientific focus

This project area aims to integrate novel regulators of angiogenesis into the network of currently known mediators involved in vascular growth, remodeling or regression. Knowledge on the molecular modulation of angiogenesis will be combined with molecular, cell- and stem cell-based approaches to initiate repair and in vivo regeneration of cardiac and pulmonary tissue. New angiogenic and angiostatic factors to be analyzed in the context of angiogenesis networks currently include FSAP, a protein with importance for hemostatic events, cytochrome P450 products, homeobox genes, soluble EGFL7 as key regulator of endothelial tube formation and the angiogenic deacetylase sirtuin 1. To pinpoint key regulators of regeneration of the lung alveolar compartment, transcriptome and proteome wide screens will be undertaken using various animal models of induction and arrest of alveolarization. In addition, regulators thought to play key roles in the regenerative growth of acinar tissue and alveolar maintenance will be analyzed for their role in morphogenesis and their suitability as targets for new intervention strategies, such as forkhead transcription factors, HIF2α and the HIF-VEGF-VEGFR-2 axis. Resident peripheral lung stem cells will be identified, characterized, traced in vivo, purified for in-vitro manipulation including transfection with specific promoter driven reporter gene expression and somatic gene transfer and employed for induction of lung tissue regeneration. Molecular mechanisms of maladaptive hypertrophy of the left and right ventricle to enhanced afterload will be investigated, and strategies for reversal of these abnormalities and reconstitution of normal contractile function be evaluated. This project area overlaps with the scope of area 1 which is focused on circulating and resident progenitor and stem cells, but goes beyond this specific view to integrate all aspect inherent in manipulation of angiogenesis and induction of repair and regeneration in heart and lung tissue. The studies planned in this field will profit from the incoming Max-Planck chairs for Vascular Development and Patterning and Alveolar Development and Remodeling and the ECCPS based Junior Research Group for Developmental Cardiogenetics and Signal Transduction, all dedicated to combine deciphering of functionally integrated morphogenetic signaling network in cardiovascular and pulmonary development with the exploitation of this knowledge for regenerative medicine.

Cooperative projects planned by the current ECCPS faculty
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Project Area D Matrix Regulation and Fibrosis

Prof. Dr.Günther, Andreas / Prof. Dr. Pfeilschifter, Josef

Vascular and interstitial remodeling with subsequent accumulation of fibrotic tissue constitutes an increasingly appreciated pathomechanism of lung and heart failure. Non-controlled (maladaptive) interstitial remodeling is characterized by two pathological hallmarks in both the heart and the lung i) an increased deposition of extracellular matrix (ECM) molecules mostly comprised of fibrillar collagens, and ii) an increased accumulation of activated tissue (myo)fibroblasts. These changes coincide with progressive loss of functional parenchymal cells (cardiomyocytes and alveolar epithelial cells, respectively), and at the same time represent the main therapeutic angle for inhibiting or even reversing fibrotic transformation of the heart and lung. Three key mechanisms are currently discussed to lead to the increased pool of activated (myo)fibroblasts: i) local fibroproliferation of resident heart and lung fibroblasts, ii) recruitment and differentiation of circulating precursor cells, and iii) generation of fibroblasts via epithelial-mesenchymal transition (EMT). A variety of upstream trigger mechanisms may activate any of these three mechanisms of (myo)fibroblast accumulation, such as inflammatory pathways including TNF-α-signaling, epithelial, endothelial and myocyte injuries by reactive oxygen species (ROS), mechanical stress, secretory defects, hypoxia/ischemia, and even medical measures (radiation, drugs). Independent of the initial trigger mechanisms, however, the final common pathway of tissue fibrosis is conserved and includes overexpression and increased activation of profibrotic cytokines/growth factors such as PDGF, thrombin, endothelin-1, IGF-1, CTGF and, most importantly, TGF-α.

Scientific Focus

This project area seeks to comprehensively characterize and offer novel treatment options for heart and lung fibrosis by employing cutting edge research in collaboration of four main areas: i) investigation of upstream trigger mechanisms (hypoxia, secretory defects, ER stress, radiation, TNF-α), ii) delineation of the contribution of local fibroproliferation, circulating precursor cells, or EMT to heart and lung fibrosis, iii) identification of organ-specific regulatory principles and aggravating mechanisms of matrix turnover, and and iv) determination of the efficacy of novel treatment options such as local delivery of siRNA or somatic gene transfer (aerosolized nano-carriers) in heart and lung fibrosis. State-of-the-art research strategies will be applied to achieve these objectives including molecular biology techniques, primary (including human) cell culture and co-culture models, cell signaling analysis, advanced analysis of ECM components. Novel disease-relevant targets will be investigated in animal models of fibrosis (e.g. bleomycin, radiation, HPS) and in clinical trials in fibrosis patients, such as those in idiopathic pulmonary fibrosis being in preparation (inhaled siRNA targeting the TGF-s pathway) or ongoing (inhaled heparin). Given the unmet challenges of this research area, the ECCPS will fund a Chair for Matrix Remodeling and a Junior Research Group for Vascular Matrix Biology, which will further enhance the expertise in this field.

Cooperative projects planned by the current ECCPS faculty
Investigation of upstream trigger mechanisms
Delineation of the contribution of local fibroproliferation, circulating precursor cells, or epithelial-tomesenchymal transition
Identification of main regulatory principles of matrix turnover and aggravating mechanisms
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Project Area E Ischemia, hypoxia, and reactive oxygen species

Prof. Dr. Brandes, Ralf Peter / Prof. Dr. Weissmann, Norbert

Shortage of oxygen, as occurs in ischemia or during hypoxia, can evoke life-threatening conditions. However, the underlying pathophysiological mechanisms of the cellular, tissue, and organ response and adaptation to a lack of oxygen remain to be fully elucidated. Ischemia and hypoxia are directly linked to alterations of the cellular redox state, reactive oxygen species (ROS) generation and metabolism. Excessive oxidative damage during reoxygenation has been shown to cause reperfusion injury. However, ROS are suggested not only to have pathophysiological effects, but to play an important role as signaling molecules, e.g. for coping with loss of oxygen, but also in a myriad of cell functions. Hypoxia, ischemia, and ROS are key players in the development of a variety of diseases with major socioeconomic impact such as coronary artery disease, cardiac hypertrophy, emphysema, sleep apnea and lung fibrosis. It is assumed that interference with the formation of ROS may delay the onset and/or prevent such diseases. Future research in this field should be aimed at identifying the specific mechanisms involved in the generation, signaling and action of ROS in order to achieve the goal of developing tools to specifically interfere with individual pathways affected by ROS

Scientific focus

This project area aims to identify the (patho)physiological mechanisms associated with or provoked by a) ischemia, b) hypoxia and c) changes in ROS generation from the subcellular and molecular to the organ level. Organ and cell models (e.g. ischemia and reperfusion in isolated perfused mouse lung and isolated cardiomyocytes, investigations in isolated fibroblasts and smooth muscle cells from the systemic and pulmonary circulation), up to intact animal models (e.g. mice exposed to cyclic hypoxia, chronic hypoxia, or cigarette smoke) and down to the molecular models (e.g. ROS-dependent regulation of eicosanoid formation by lipid binding domains) will be employed to address these objectives. Moreover, different projects will address the regulation of the various isoforms of the hypoxia-inducible transcription factor (HIF) that is thought to be a key player i) for the defense against the detrimental effects of hypoxia, and ii) for development of pulmonary hypertension as well as tumor formation. Redox regulation, ROS release/generation and their interplay with reactive nitrogen species will be investigated to assess the role of ROS in physiology (e.g. regulation of vasoreactivity in the lung, pulmonary oxygen sensing) as well as in pathophysiology (e.g. aging of cardiomyocytes, ischemia/reperfusion in heart and lung disease and endothelial dysfunction in chronic obstructive pulmonary disease and sleep apnea). In this respect the role of endogenous inhibitors of nitric oxide generation as well as the sources (e.g. phagocytic as well as nonphagocytic NADPH oxidases) and kinetics of ROS release (e.g. quantified by ESR spectroscopy) will be addressed in different models. The challenging aim of this project area is to generate a detailed map of the consequences of ROS production, hypoxia and ischemia in heart and lung disease in order to develop new therapeutic approaches. This research area will be further supported by the incoming Max-Planck chair for Vascular Signaling and Remodeling.

Cooperative projects planned by the current ECCPS faculty
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Project Area F Infection, inflammation and control of barrier function

Prof. Dr. Lohmeyer, Jürgen / Prof. Dr.Zacharowski, Kai

Cardio-pulmonary endo-/epithelial surface areas are highly sensitive to injury by maladapted inflammation elicited by both non-infectious and infectious triggers. Loss of endo-/epithelial interface integrity impairs barrier function and may cause organ failure. Due to its large epithelial surface area the lung is prototypically affected by infection-triggered inflammation with pneumonia being the most frequent cause of infectious death worldwide. The local inflammatory host response induced by microbial contact is pivotal for infection control but as double-edged sword also causes auto-aggressive tissue injury and contributes to organ failure. The identification of the molecular checkpoints in microbial host interplay that discriminate protective host defence activity from injurious inflammation is essential for the design of clinical intervention strategies that target selective inflammatory pathways.
Though also impaired by infection triggered inflammation in septic disease, heart organ function is much more commonly affected by non-infectious activation of inflammatory pathways triggered by release of endogenous danger signals in metabolic disorders or myocardial ischemia-reperfusion. Such endogenous inflammatory activation events significantly contribute to acute capillary leakage, progression of coronary heart disease and the outcome of reperfusion treatment of acute myocardial infarction. The molecular identification of endogenous inflammation inducers, corresponding sensors and related downstream signalling cascades can be expected to identify targets for new therapies in non-infectious heart disease.
In both organs, heart and lung, infectious or non-infectious activation of inflammatory pathways impair the delicate functions of endothelial and epithelial barrier surfaces in the compartmentation of water, solutes and cells. The precise molecular steps by which unbalanced inflammation promotes loss of barrier function as well as the role of compensatory pathways stabilizing barrier control have not yet been elucidated. Understanding the molecular pathogenesis of inflammation-induced barrier dysfunction is essential for therapeutic strategies specifically targeting cardio-pulmonary endo- or epithelial barrier functions and fluid clearance.

Scientific focus

This project area aims to elucidate the molecular interplay between inflammation events and endo-/epithelial interface structures in the cardio-pulmonary system. This intends to decipher the molecular cross talk between infectious attack and host defence, to analyse inflammatory and inflammationlinked mediators of endo- and epithelial cells, and to identify signaling pathways underlying failure of barrier function. Genomic, proteomic, cellular and functional (loss and gain of function) approaches will be used to identify key molecules and effector cells in infection and non-infection triggered inflammation and to discriminate protective from injurious inflammatory signalling cascades. In addition, compensatory protective pathways of heart and lung parenchymal cells will be evaluated for molecular checkpoints that allow their selective activation to preserve or rescue cardio-pulmonary organ function. This comprehensive approach integrates investigations on the cellular level (cardiomyocytes, endothelial cells, pulmonary cell constituents, in vitro endo-/epithelial barrier models), on the level of isolated organs (organ models of septic heart or lung failure, models of ischemia/reperfusion-induced heart and lung injury), in whole animals (acute and chronic lung/heart infection/inflammation in wild-type and genetically engineered mice) and studies in patient cohorts with acute (ARDS) and chronic (COPD/emphysema, fibrosis) lung failure and coronary heart disease. Deciphering the molecular pathogenesis of infectious and non-infectious inflammatory pathways is expected to identify target molecules for novel therapies to be further assessed in preclinical and clinical studies for their potency to control cardio-pulmonary inflammation, and to maintain or enhance barrier properties. The activities in this research area will be strongly further supported by the incoming Max Planck chair for Vascular Signaling and Remodeling.

Cooperative projects planned by the current ECCPS faculty
Control of infection
Control of inflammation
Control of barrier function
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Project Area G Vascular consequences of metabolic syndrome

Prof. Dr. Fleming, Ingrid Jeanette / Prof. Dr. Preissner, Klaus Theodor

Metabolic syndrome defines a pathological intermediate state of insulin resistance between normal metabolism and type 2 diabetes, and it is prevalent in more than 20% of the adult population. The likelihood to develop metabolic syndrome increases with higher body mass index (particularly visceral obesity), smoking, physical inactivity as well as postmenopausal status or advanced age, and a constellation of risk factors including dyslipidemia, hypertension, hyperglycemia, and as yet poorly defined genetic components, predispose patients towards a proatherothrombotic state. Together with other well-known sources of hormones and cytokines, adipose tissue can be considered as an endocrine organ that produces numerous adipokines such as TNF-α, plasminogen activator inhibitor type 1, leptin, adiponectin, resistin. Besides their important signaling function with regard to changes in fat tissue mass, fuel usage and energy status, these circulating factors (and their receptors) are intimately involved in vascular homeostasis and the inflammatory status and can directly modulate endothelial cell functions. Moreover, activation of the renin-angiotensin system is closely linked to insulin resistance and adipokine levels. Recent studies implicate that calcium homeostasis in the vasculature is closely associated with a regulatory cytokine system involving RANKL and osteoprotegerin in order to control vascular calcification. Finally, instability of tissue integrity and tissue damage leads to exposure of intracellular material to blood components, and here, extracellular nucleic acids were recently shown to exert potent humoral and cellular effects possibly associated with a hypercoagulable state. These factors and their cellular receptors represent key players with respect to molecular links between metabolic syndrome and cardiovascular diseases and are attractive new targets for novel therapeutic strategies.

Scientific focus

The aims of this project area are to identify the molecular and cellular mechanisms by which adipokines, advanced glycation end products (AGE), extracellular nucleic acids (particularly RNA) and calcification regulatory components contribute to the development of insulin resistance, vascular inflammation and the progression of cardiovascular disease. Conversely, the role of mediators of vascular tone and homeostasis such as angiotensin or coagulation factors will be deciphered to understand their contribution in metabolic syndrome. To this end, the signaling activity of intra- and extracellular AGE, extracellular RNA and adipokines (such as leptin) as well as the contribution of the forkhead transcription factors in cardiovascular and lung tissue will be analyzed. Consequences of insulin-sensitizing therapy for endothelial and monocyte/macrophage function, vascular homeostasis, platelet-endothelial interaction and the progression of atherosclerosis (in animal models and where possible in humans) will be focused on. The scope of this project area is extensive and integrates investigations at the molecular and cellular level (e.g. mechanisms addressing receptor-mediated cellular functions of adipokines, extracellular RNA and AGE), at the level of isolated organs (e.g. consequences on autacoid production and endothelial cell functions), as well as in animal models (genetic and induced diabetes in rats and mice to identify mechanisms of leukocyte adhesion/transmigration that relate to the predisposed conditions of hyperglycemia) and in humans (clinical evaluation of adipokine levels, insulin resistance and vascular function in patients treated with ACE inhibitors, AT1 receptor blockers or insulin-sensitizing agents). This integrated approach is essential for the development of new strategies for the prevention and treatment of vascular consequences of metabolic syndrome. Given the broad scope and large workload as well as the clinical and economical importance of this project area, the ECCPS plans to fund a Chair for in Vascular Function and Metabolic Syndrome to address the vascular consequences of diabetes and obesity and to complement the expertise of the initial participants.

Cooperative projects planned by the current ECCPS faculty
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Project Area H Molecular senescence - aging of the cardio-pulmonary system

Prof. Dr. Brüne, Bernhard

Aging is the major contributor to morbidity and mortality of cardiovascular and pulmonary diseases. In the heart, reduction of coronary reserve and myocardial contractility are frequently encountered in elderly patients. In the lung, “senile” emphysema, a decrease in the vasodilatory and recruitment reserve of the pulmonary vasculature and immunosenescence of the alveolar compartment with susceptibility to pneumonia are common occurrences. Heart, vascular and lung function requires a balanced rate of cell loss and cell renewal/regeneration, which appears to decline upon senescence, thereby handicapping physiological regeneration and repair mechanisms with resultant decline in organ function. Key processes currently known to underlie such age-dependent alterations include the increase in reactive oxygen species (ROS), disturbed energy metabolism, telomere attrition, loss of telomerase reverse transcriptase activity, loss of cell cycle control mechanisms, and exhaustion of the supply of progenitor or stem cells for organ repair. Despite the fact that cardiovascular and pulmonary diseases are prototypic for age-related degenerative illness, the molecular mechanisms underlying aging in the cardio-pulmonary system are largely unknown.

Scientific focus

The aims of this project area are to identify the aged-dependent mechanisms involved in cardiovascular and lung degeneration. This project area will investigate: (i) the role of telomere attrition, telomerase activity and telomere-associated proteins for the repair/renewal capacity of vascular and progenitor cells from patients with cardiovascular and pulmonary diseases, (ii) the contribution of oxidative stress to cardiovascular aging and (iii) the implications of a disturbed energy metabolism for cardiovascular aging. The role of ROS generated by NADPH oxidases and mitochondria as well as the determinants for cytosolic/mitochondrial interactions in aging of vascular cells and cardiomyocytes will be determined and compared. In several animal models, the potential impact of oxidative stress generated by different sources will be dissected and the impact of mitochondrial DNA mutations on aging processes will be investigated (e.g. AZT/d4T- and doxorubicin-induced damage of mitochondrial DNA, gp91phox-deficient mice, SOD2 mice, Dwarf mice). An unbalanced energy metabolism occurring during the process of aging is likely to result in a change in expression profile in vascular cells, progenitor cells and cardiomyocytes. Interesting candidates are the silent information regulator gene family (SIR), the respiratory chain components of complex I and the peroxisome proliferation activated receptor γ (PPARγ). This project area will also assess age-related processes in the lung: (iv) the role of a decline of alveolar phagocyte recruitment capacity (monocytes, PMN, dendritic cells) for loss of the immunocompetence of the alveolar compartment, (v) the hypothesis that reduced expression of the HIF-2alpha-VEGF axis, representing a central maintenance program for the pulmonary vasculature, underlies the loss of alveolar capillarity in aged mice and (vi) the hypothesis that senile emphysema is linked with loss of compensatory/regenerative acinar growth. Based on the mechanistic insights awaited from these studies, we plan to develop therapeutic strategies to improve age-associated impairment of heart and lung structure and function by fostering stem/progenitor cell based renewal of critical organotypic cells and regeneration of structural integrity. The engagement of the ECCPS in this most challenging field is underscored by the fact that two new funded research groups will address topics of aging in the cardio-pulmonary system (W3 chair for Cardiac Aging, Junior Research Groups for Molecular Mechanisms of Emphysema and Lung Aging).

Cooperative projects planned by the current ECCPS faculty
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Project Area I Molecular signature analysis for individualized therapy

Prof. Dr. Ghofrani, H. Ardeschir / Prof. Dr. Hamm, Christian W.

In heart and lung diseases, current assessment of a patient’s prognosis and therapeutic decision making largely follow evidence-based criteria and the results of studies performed with large patient collectives. However, there is substantial heterogeneity in most of the studied collectives and individual characteristics may strongly affect the course of disease. In neoplastic disorders, molecular signature analysis has proven useful for the determination of prognosis and response to treatment. It is the goal of molecular signature analysis to identify patterns of gene expression and their translation into phenotypic features which are associated with meaningful clinical parameters such as specific etiology, prognosis or therapy response. This approach is expected to provide diagnostic or prognostic precision on a level not currently achieved or achievable on the basis of standard clinical information, and to establish a basis for tailoring individual treatment. Pre-existing experience of ECCPS members in this field lies in the characterization of circulating biomarkers of coronary artery disease such as troponin, CD40L and PlGF, and the cDNA microarray expression profiling of the progression from severe pneumonia to sepsis. Along this line, this project area focuses on i) transcriptome analysis, ii) proteome and biomarker analysis and iii) in-vivo imaging of molecular events in heart and lung diseases, aiming to shape and validate patterns of molecular signatures for individualized assessment of prognosis and guidance of therapy. Variations on the genetic level (e.g. polymorphisms, pharmacogenetics), being in the center of individualized approaches in several other centers, will not represent the focus of this area.

Scientific focus

This project will focus on coronary artery disease, cardiomyopathy, pulmonary hypertension, lung fibrosis and severe pneumonia, diseases for which there is broad expertise in the ECCPS. At the transcriptome level, initial broad spectrum gene expression profiling with large scale microarrays and linkage with clinically meaningful variables (specific etiology, prognosis, response to therapy) is being undertaken to develop customized chips focusing on circumscriptive molecular signatures with high specifity and sensitivity. Use of tissue samples may be mandatory, but replacement by peripheral blood leukocyte samples or whole blood transcriptome analysis, the utility of which has previously been shown, is an important goal to reduce the invasiveness of the approach. At the protein level, mass spectrometry and chip technology will be employed in a non-hypothesis driven approach in correspondence with the transcriptome approach. In addition, by using explorative screening and hypothesis-based strategies, novel circulating peptidergic biomarkers will be studied for their suitability as markers of disease progression and specific risks. Progress in the in-vivo molecular imaging field is critically dependent on the further technical development of respective technologies (e.g. MRT, PET), and the identification of suitable target structures to be addressed. Most of the progress in this field is thus to be expected in the later stages of the ECCPS funding. Tailored therapy in cardio-pulmonary diseases is still in its earliest stages. The ultimate potential of transcriptome- and proteome-based molecular signature analysis is individualization of management and therapy guidance in patients with heart and lung disease. Though no new professorship is presently planned to be installed in this area, the strategies for individualized therapies will also largely profit from the recruitment of new groups planned for the ECCPS.

Cooperative projects planned by the current ECCPS faculty
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Platform A: Techniques and Technology Development

Level Techniques ECCPS Scientists
Genomics, Transcriptomics cDNA microarray platform including bioinformatics, customized chip manufacturing, DNA sequencing, SNPs, STRs, chromatin immunoprecipitation (ChIP) technology, yeast two/three-hybrid screens, microarrays for protein-DNA interaction (protein – and dsDNA microarrays), RNA fin-gerprinting/RAP-PCR, promoter luciferase assays, SNP pyrosequencing laser-mediated micro-dissection including perivascular genomic analysis Bein, Braun, Chakraborty, Dimmeler, Euler, Geisslinger, Hänze, Mäller-Ladner, Pfeilschifter, Pingoud, Preissner, Sedding, Steinhilber, Urbich
Proteomics MALDI-TOF-MS, MALDI-TOF/TOF-MS, ESI-MS/MS, SELDI-MS, Nano-LC-ESI-MS/MS, protein profiling on antibody chip, DNA-assisted protein chip, ELISPOT micro 2-D protein-analysis, tissue microassay, peptide mapping and sequencing, cross-linking analysis, phosphoproteome, subcellular fractionation, recombinant protein expression in cell lines, phage-display screen Eickelberg, Fink, Geyer, Hackstein, Haendeler, Müller-Esterl, Preissner, Pingoud, Santoso, Schäfer, Sedding, Pfeilschifter
Lipidomics, Glyconomics HPTLC, ESI-MS, LC-MS/MS, 2D-HPLC, GC/MS, MALDI TOF/TOF-MS, nano-ESI-MS/MS, carbohydrate composition and linkage analysis, LC-MS/MS Geisslinger, Geyer, Günther, Mayer, Pfeilschifter, Steinhilber,
ROS/NO Detection ESR spectroscopy, in-situ remission spectroscopy, chem.-iluminescence, single cell microfluorometry Brandes, Fleming, Kummer, Sauer, Steinhilber, Weissmann, Wenzel
Imaging – molecular FRET, BRET, confocal microscopy, automated high throughput in situ hybridization, in-situ PCR, immunocy-to(histo)chemistry, cell-edge-detection system for determination of contractile function, cell coupling; fluorimetric second messenger detection, activatable smart probes, live cell imaging Brandes, Braun, Fleming, Kummer, Liebner, Müller-Ladner, Noll, Santoso, Sauer, Schäfer, Schlüter,
Imaging – small animals Small animal NMR, micro-CT, flat-panel volumetric CT, mouse echocardiography Braun, Mayer, Rose, Schermuly, Sedding
Imaging – morphometry Software-assisted vascular morphometry (medial wall thickness, lumen area, degree of muscularization), alveolar morphometric routines (septal wall thickness, mean alveolar intersept and airspace) Schermuly, Weissmann
Level Techniques ECCPS Scientists
Imaging – clinical Cardiac MRT, IVUS, MS CT, virtual imaging, 3-D echocardiography Fichtlscherer, Hamm, Schächinger, Tillmanns, Zeiher
Cytometric profiling FACS-based multiparametric immunophenotyping/sorting , high volume immunomagnetic cell sorting (autoMACS); analysis of cell-specific gene and protein expression (multicolour fluorescent antibodies) in complex cell samples Aicher, Bein, Braun, Dimmeler, Hackstein, Henschler, Liebner, Lohmeyer, Noll, Schmitz,
Transgenic mouse facility Mouse ES cell bank, generation of transgenic mice, knock-out, knock-in mutants, generation of cell-type-spe-cific temporally-controlled somatic mutants, mouse genotyping, archiving of mouse models; link to the European Mouse Mutant Archive (EMMA) and the German Gene Trap Consortium (GGTC) via NGFN Braun, Chakraborty, Euler, Liebner, Schlüter, von Melchner
Transfection technology Adeno-, retro-virus and bacteria mediated gene transfer, liposome based gene transfer technologies, PEI-DNA aerosol technology, aerosolized nanocarriers for gene transfer, ribozymes, antisense technology, VP22-mediated proteintransfer Chakraborty, Dimmeler, Euler, Fink, Fisslthaler, Fleming, Hänze, Liebner, Müller-Ladner, Noll, Pingoud, Schmitz, Sedding, Steinhilber, Urbich
Gene silencing by RNA interference siRNA manufacturing, siRNA aerosolization and vector technology, conditional RNAi in mice (Tet control, Cre/lox control), lentiviral siRNA transfer Braun, Eickelberg, Fisslthaler, Hänze, Kummer, Müller-Ladner, Schermuly, Schmitz, Sedding, Vornlochner
Mouse cardio-pulmonary phenotyping Invasive, non-invasive and telemetric hemodynamic assessment, echocardiography, mouse lung function testing Brandes, Braun, Kummer, Schermuly, Weissmann
Mouse models of heart and lung disease Models for cardiac ischemia and myocardial infarction, pressure induced left heart failure and right heart hypertrophy, atherosclerosis, post-angioplasty restenosis, cardiac allograft vasculopathy, pulmonary hypertension (hypoxia, monocrotaline, 5-HTT-/-), lung fibrosis (bleomycin, amiodarone, radiation, HPS, SPC-/-), ARDS (lavage, oleic acid), ventilator-induced lung injury, emphysema, sleep apnea (period hypoxia), lung tumor and metastasis. Mixed chimeric bone marrow transplantation, in-vivo stem cell tracing Brandes, Braun, Euler, Fleming, Grimminger, Günther, Kummer, Mayer, Plate, Ruppert, Schäfer, Schermuly, Schlüter, Sedding, Voswinckel, Weissmann
Level Techniques ECCPS Scientists
Angiogenesis models In-vitro assays (Fibrin and Matrigel assays), Matrigel plug assays in mice, hind limb ischemia model, tumor angioge-nesis models, ES cell angiogenesis assay Acker, Fleming, Liebner, Plate, Sauer, Voswinckel
Stem cell technologies Large scale murine ES-cell production induced ES-cell differentiation into endothelial cells, epithelial cells, smooth muscle cells and cardiomyocytes. Targeted manipulation of cardiomyocyte development. Purification of human and murine endothelial progenitors, circulating fibrocytes, smooth muscle cell progenitors, mesenchymal stem cells, hematopoietic stem cells. In vivo tracing of stem cell progeny with reporter-transgenes, TK constructs, and radioactive labeling. GMP facilities and permission for the isolation and cultivation of human stem cells for clinical use (production license HA-FE-504/A). Braun, Dimmeler, Henschler, Sauer, Sedding, Voswinckel, Seifried
Human primary cell banks Facilities for human embryonic stem cell technology and bone marrow-derived cell function, banks of human primary alveolar and bronchial epithelial cells, lung endothelial cells, pulmonary vascular fibroblasts, pulmonary vascular smooth muscle cells. Banks of patient-derived human bone marrow-derived progenitor cells Dimmeler, Lohmeyer, Rose, Sauer, Voswinckel, Zeiher
Human tissue banks European PH Tissue Bank; German Lung Fibrosis Tissue bank, Lung Emphysema Tissue Bank; DNA and serum (biomarker) banks from patients with acute coronary syndromes; DNA bank for identification of genetic determinants of progenitor cell function Bohle, Dimmeler, Grimminger, Günther, Hamm, Sauer, Voswinckel, Zeiher
Registries of patient cohorts European PH registry, German Lung Fibrosis Registry, EUSTAR (European Scleroderma Trial and Research Group) 3500 patients, DNSS (German network for systemic sclerosis) 1500 patients. Günther, Müller-Ladner, Seeger
Clinical Trial Units (see Platform B) ZAFES Clinical Study Center, PH Trial Unit, Lung Fibrosis Trial Unit, Emphysema and Sleep Apnea Trial Unit, Cell Therapy Center including GMP facility for cell isolation Geisslinger, Ghofrani, Grimminger, Günther, Schächinger, Zeiher
Intern. Networks coordinated by ECCPS REPAIR-AMI, EU PH Trial Network, CapNET, SepNET, EU Lung Fibrosis Net, EUSTAR (European Scleroderma Trial and Research Group) 3500 patients, DNSS (German network for systemic sclerosis) 1500 patients, German Network for Mechanical Ventilation, NGFN Infection & Inflammation Network Chakraborty, Ghofrani, Seeger, Grimminger, Günther, Müller-Ladner, Zeiher
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Platform B: Technology Transfer and Pharmaceutical Exploitation

Network for Clinical Trials (NCT)

Members of the ECCPS faculty hold leading positions in the Center for Drug Research, Development and Safety - ZAFES , and its subsidiary the “Clinical Study Center Rhine-Main”, both at the University of Frankfurt. The same is true for the Clinical Trial Center focused in the field of pulmonary medicine, which is based in Giessen, the UGLC.
These centers have agreed to their alliance in the new “Network for Clinical Trials (NCT)” within the frame of the ECCPS. This clinical trial center will have access to over 10.000 patient beds (in university and teaching hospitals) and is thus optimally outfitted for the performance of clinical trials at all levels (I-IV). It will offer expert assistance for:

Network for Technology Transfer (NTT)

In a complementary approach, the TransMIT Society for Technology Transfer in Giessen , the Society for Innovation Nordhessen and INNOVECTIS (Society for innovation service in Frankfurt), already allied in the so-called “Hessische Intellectual Property Offensive (HIPO)”, and the Frankfurt Innovation Center Biotechnology will be linked within the framework of the ECCPS to form a “Network for Technology Transfer (NTT)”. By means of HIPO the ECCPS will participate in the “Genome Marketplace” which is a central internet platform for all German technology transfer units (www.). This platform serves as interface to industry and should interest be expressed, links to the relevant scientists are established via the local transfer units. The NTT will provide ECCPS members expert assistance and/or perform remittance work with regard to patent issues, intellectual property protection, commercialization and company foundation.

The NCT along with NTT will provide a platform covering all aspects of the drug development process. Moreover, virtually all members of the ECCPS faculty have already established strong links with pharmaceutical or technological companies, which guarantees an excellent basis for communication with industry. Examples of such public-private partnerships are the funding of the International Graduate Fellowship program Molecular Biology and Medicine of the Lung by a grant from Altana (Altana Inc., Konstanz) and the endowment of a Chair for Pulmonary Hypertension by Pfizer International.

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Platform C: Educational and Training Activities

Promotion of young researchers The advancement of junior scientists is a main priority for the ECCPS. A sub-committee for Training and Education will be convened to take responsibility for Platform C which addresses this issue. Measures already being or planned to be undertaken include:

Graduate schools and international postgraduate programs

Members of the ECCPS currently run five international postgraduate programs in the field of heart, lung and vascular biology (for details see Platform C). Two of these schools are already linked with international partners (Stockholm and New York). These programs receive hundreds of applications from all over the world in each announcement, making a selection process mandatory and resulting in percentages of international students of >50%. The graduate programs in Giessen will be incorporated into the International Giessen Graduate School for the Life Sciences (GGL), those in Frankfurt into the Frankfurt International Research School for Translational Biomedicine (FIRST) (a separate application for support within the Excellence Program has been filed). A PhD - MD/PhD program has been set up by the medical and veterinary medicine faculties in Giessen and is open to Master students in the fields of biomedical and natural sciences. Thus, both Giessen and Frankfurt already possess strong and internationally recognized platforms for postgraduate training in cardiovascular and pulmonary medicine. The link between the ECCPS and these successful graduate school programs will further foster the reputation of these programs, attracting the most talented international students interested in this field of medicine. To further strengthen this concept, collaboration between the Max-Planck Institute (Bad Nauheim) and the universities of Giessen and Frankfurt is planned to establish an International Max Planck Research School for Heart and Lung Research in Bad Nauheim (IMPRS-HLBN).

Postgraduate ZAFES qualification course

This program will be open to students associated with the ECCPS and provides basic knowledge on key aspects of drug research, development and safety that are not covered by regular courses.

Post-doctoral stipends

The ECCPS will finance a pool of post-doctoral or transitional stipends, in order to support promising young scientists who have finished their postgraduate program. This program is envisaged as a short term support to bridge the gap until extramural funding from national and international agencies (e.g., DFG, Emmy Noether program, Humboldt program, EU Marie Curie program) is obtained.

Independent Junior Research Groups

Several such groups have already been installed in Frankfurt and Giessen, and more will be financed by the ECCPS budget. This is in line with the philosophy of the ECCPS to promote early independency of young scientists. Tenure track options for the leaders of these Junior Research Groups will be provided, in accordance with the guidelines recently suggested by The German Science Council (“Wissenschaftsrat”). Altogether, the ECCPS offers a stimulating research environment for Junior Research Group leaders, and we expect to attract more once our excellence cluster is fully established, including holders of Heisenberg and Emmy Noether fellowships and Kovalevskaja prize winners (4 such awardees currently work in ECCPS groups in Frankfurt and Giessen).

In addition, the sub-committee for Training and Education will organize training programs and technical workshops as well as postgraduate workshops to promote the exchange of expertise within the ECCPS. Training programs in management and entrepreneurship, which will be of particular interest to researchers aiming to operate at the interface between academia and industry, will be organized in collaboration with Platform B.

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