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Aber wo ist sie? Wie von einem Strudel erfasst, wird Vainsteins in diesen Fall hineingezogen, in dem es um Scheinehen, Drogen und Prostitution geht. Dort trifft er auf seinen Gegenspieler, den Vertreter einer feindlichen Macht. Und das kurz vor der Landtagswahl, in der es die absolute Mehrheit zu verteidigen gilt. Welchen Einfluss hat eine Astrologin auf die bayerische Politik?
Oder handelt es sich gar um politischen Terrorismus? Er hat vergeblich versucht, den Trennungsschmerz nach seiner Scheidung mit Alkohol zu stillen. Aber Beckmann glaubt nicht an diese Theorie. Hauptkommissar Bernd Freitag, noch nicht im Dienst in Oranienburg und muss doch schon los. Immer wieder tappen sie im Dunklen, nie eine wirkliche Spur. Bernd beginnt von vorn mit dem group und neuen Ideen, sie finden was once im Harz, wieder ein Kopf im Wald, aber immer keine Spuren. Bis etwas passiert, sein Nachbar verschwindet, endlich kommt Bewegung in diese unselige Geschichte. But now, after four years of research, a team of scien- tists led by Thomas Jentsch have found the answer.
In an automated screening process activated chloride flux across the cell mem- at the MDC; now at the University of Mainz. Why the heart fails Defects in splicing are implicated in a number of serious genetic diseases, like the heart disease dilated cardiomyopathy DCM. This condition is marked by an en- larged, weakened heart and is responsible for about a third of deaths from congestive heart failure. They provided a detailed account of the operation of RBM20, which is preferentially present in the heart and orchestrates a large number of target revealed that it was located in introns, from where it tells the spliceosome to remove a nearby exon, thus shortening the molecule.
But the defective RBM20 version fails to remove the exon and instead creates RNA with extra segments, resulting in proteins molecules. Ultimately, the findings are clinically relevant. Journal of Clinical Investigation 8: Start region shown to be unidirectional To enable enzymes to grab ahold and start transcribing a gene at the right place, the DNA contains recognition sequences, so- called promoters, which are located imme- diately upstream. Ever since researchers began using high-throughput sequencing technology to precisely investigate gene ex- pression patterns, they have believed that a large percentage of promoters are not uni- directional.
Their stud- ies show that a central part of promo ters, the core promoter, is intrinsically unidirec- tional, and that transcripts of the opposing DNA strand arise from their own core pro- moters. Using high-throughput experiments and various analytical procedures, the re- searchers determined that in fact about 40 percent of the genes have two opposite core promoters at variable distances. Since reverse-directed core promoters are common but not universal, the researchers presume that these at least partially help to regulate gene transcription.
Molecular Cell Jan The mologous recombination and thus of pre- Cas9 by up to eightfold. Nat Biotechnol 24 Mar The affected individuals have heredi- tary hypertension, unusually short fingers before the age of fifty if their hypertension goes untreated. This disease, which afflicts this and five other families not related to entists have thus discovered the first Men- each other, causes six different point muta- tions in the PDE3A gene.
These mutations lead to high blood pressure and shortened bones of the extremities, particularly the metacarpal and metatarsal bones. The sci- delian hypertension form not based on salt reabsorption in the kidneys, but instead is more directly related to the structure and function of the vascular wall. Nat Genet 47 6: This animal model can be used to test the therapeutic suitability of T cell re- ceptors and antigens, which is an important prerequisite for the development of clinical applications.
Targeting human melanoma neoantigens by T cell receptor gene therapy. Journal of Clinical Investigation 25 Jan This question is at the core of Nir Fried- tems biologist was granted a Humboldt Research Award that enabled him to con- tinue his work in Berlin. Since , 37 principal investigators and 20 PhD students have been involved, re- sulting in 21 papers so far. For their thesis projects, students have a main supervisor at their home institute and a co-mentor abroad. Joint events such as symposia, winter schools and PhD retreats are intended to offer a space for the two each other.
Many principal investigators at the MDC have forged collaborations with visits, they are actively contributing to the Helmholtz-Israeli Cooperation in Per- sonalized Medicine through two projects: An emerging group Israel might not be a large country, but it Israeli scientists. But not all patients acids; they are found in oily fish such E veryone knows about omega-3 fatty will benefit from a change of diet.
It is supposed prevent atrial fibrillation and reduce the to bypass the intermediate step and act directly on the receptors of heart muscle cells. The researchers hope that this will risk of heart failure and strokes. The sub- stance has already proved effective in ani- mal models. A phase 1 study on healthy hu- man volunteers began in March The biochemist and his colleagues are now.
MDC re- searchers made a key contribution to two drugs that came on the market in Shire and Blincyto Amgen. Patients lack a protein — known as von Willebrand factor — that is crucial for normal blood clotting. Blincyto, on the other hand, is an immuno- therapy against a very aggressive form of blood cancer B-cell acute lymphoblastic leukemia. The bone marrow of these pa- tients produces too many immature white blood cells.
Rather than maturing into func- tional cells, these lymphoblasts rapidly re- produce, suppressing normal blood forma- competitive funding formats, as well as expand advisory services for start-ups in The royalties from these successes are now helping to translate other basic research transfer is a core mission of the Center.
At present, 20 research groups are working on new medical therapies or diagnostics in- tended for commercialization. Each project receives comprehensive support. The MDC law states that technology The first step is to secure the patent at an keting. In the last three years alone, 24 new patents have been filed. Ascenion and a transfer office and Ascenion jointly exam- technology transfer company based on the Buch campus which supports numerous institutions in the life sciences sector, plays a key role in this process.
The technology early stage—without intellectual property rights, nothing happens in biomedical mar- ine the market potential of the discovery and bring in external consultants to take the project to the next step, or explore opportu- nities for cooperation with other institutes and industry.
They determine whether a spin-off would be appropriate or whether the drug should be out-licensed soon. Project teams can also receive coach- ing and advice from industry experts. MDC researchers have no shortage of ideas. MDC Research Report international start-ups.
With cer, and systematically destroy it. Captain T Cell, a MDC spin-off, won against the , pounds prize money, the team will continue to develop a cancer immunothera- py that involves a platform to produce per- Center Cell Engineering Lab MD-CEL , a platform for transposon-based cell engi- neering sponsored by the Helmholtz Asso- ciation, began to work closely with science sonalized, cancer-specific T-cell receptors.
And the risk of failure is still 90 percent. Schunck is well aware of this. But right now he is especially proud to be start- the basic research to market approval is ratory, a substance that could be used to.
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Between and , the Egyptian research- er worked as a PhD student in Michael Gott- student representative and an active mem- ber of the Helmholtz Juniors network, she still found time to help refugees. With her wide range tific theories. In , Muga- that much different from the challenges ev- ery graduate student faces: More than half of them come from outside of Germany, with 42 different countries represented on campus. The stu- dents are equally varied in terms of subject: Their backgrounds cover everything from molecular biology, biochemistry, and phys- ics, to computer science, and medicine.
Neither textbooks nor care- fully developed curriculum frameworks can keep pace with the latest develop- ments and methods. The program brings teachers into the lab and allows them to spend a day immersing themselves in the world of research. They conduct experiments, listen to talks, and discuss the latest topics with researchers. The Lab Meets Teacher courses also produce teaching materials that are freely available as open educational resources.
The MDC has also spent the past 15 years working directly with young people in schools to get them excited about science. Its efforts here include running the Life sight into biomedical research each year. It Science Learning Lab, a learning center that gives over 12, school pupils an in- also sends MDC lecturers into schools to give talks, and does much more besides. They can also apply for various Helmholtz programs.
The MDC is a network designed to support women on the path to leadership positions in science. During the events, young group leaders and former postdocs who now work in industry talk about their career paths. And in the Career time at the MDC and on what came after- wards. She often considering by listening too much to others in the field. The schemes give physicians the space they need to do research during their training.
However, he adds, dents first need to acquaint themselves Internationally, just 4. It is therefore crucial that students with it and then quickly work out what they want to achieve during their time here.
This applies to postdocs in particular. However, this is not a leap everyone wants to take. The MDC Men- toring Program is designed to help post- docs make a well-informed decision about their career. Cardiovascular and Metabolic Disease Coordinator: Most cases of cardiovascular dis- eases are likely the result of contributions from multiple genes, and apparently also complex epigenetic mechanisms may lead to cardiovascular disease.
Getting an exper- imental handle on these topics and improv- ing therapeutics still is the major challenge for the next decade. An increasing number of animal models — particularly strains of rats and mice — are available and neces- sary to convert findings into relevant clini- cal tools. Research in this field sometimes finding patients with a particular profile, extrapolating from a very small number of cases, and understanding complex inter- actions within cells and cell types.
We are dealing with these challenges while con- stantly developing new types of modeling and through a thorough integration of bio- informatics with clinical and experimental approaches. The molecular analysis of car- diovascular and metabolic functions at the cellular level is a prerequisite for a mecha- nistic understanding and forms a basis for the rational implementation of novel thera- is hampered by special problems including Endothelial axial polarity measured by the position of the golgi to the nucleus of each endothelial cells red, left panel points against the direction of blood flow compare to arrows signifying flow velocity, middle panel.
The axial polarity against flow is a response of endothe- lial cells to wall shear stress right panel. Black arrowhead points to region of low flow, low wall shear and consequently divergent polarity leading to migration of cells out of the low flow segment and therefore branch regression. The Cardiovascular and Meta- bolic Diseases program has revealed some considerable key molecules and pathways involved in major processes of the cardio- vascular and metabolic systems. For exam- ple, the group of Michael Gotthardt studies the role of titin in the regulation of con- tractility in cardiac, skeletal, and smooth muscle.
Their work emphasized the role of post- transcriptional regulation in the etiology of myocardial pathology. RBM20 interacts not only with titin but potentially in a net- work of 30 genes previously linked to car- diomyophathy, ion-homeostasis, and sarco- mere biology. The group of Thomas Jentsch has a long standing interest in investigat- ing the volume-regulated anion channel VRAC channel and the relevant subunits ranging from biophysics, structure function, to cell biology, mouse models and medicine with implications for cardiovascular out- comes. Metabolic disturbances are emerg- ing as major risk factors not only of cardio- vascular but also neurodegenerative and oncological diseases.
However, the molecu- lar mechanisms that link the control of me- tabolism to other biological systems remain poorly understood. The group of Thomas Willnow is studying endocytic receptors to uncover their roles in normal physiological processes and in human disease. They dem- onstrated that LRP2, a member of the LDL receptor gene family, balances signaling of the morphogen sonic hedgehog in the de- veloping retina, and that lack of this activity results in severe overgrowth of the eyes in mouse models and patients.
Organogenesis involves multiple sequential events such as fate specification, growth, differentiation, and morphogenesis, which ultimately re- sult in the development of a functional ma- ture organ. This step-wise process relies on a coordinated and highly complex interplay 2 MDC Research Report So far, they targeted genes for the insulin receptor, the pro renin receptor, apolipoprotein E, and has also been established and successfully used to ablate genes in rats.
Understanding diseases at the molecular and cellular level is an important step in elucidating mecha- nisms that ultimately have their effects at the level of organs and organisms. The challenge remains works that influence cardiovascular and metabolic disease risk, to link molecular networks with physiological data, and to identify key regulatory nodes that can be targeted therapeutically to reduce the bur- den of cardiovascular and metabolic dis- eases in patients.
Kathrin Saar 3 of signaling events and transcriptional net- creatic progenitor cells. Importantly, aberrant developmen- the cardiovasculature, liver, or pancreas. Using latest NGS technology, Francesca Spagnoli aims at elucidating how distinct cell types like liver and pancreas can arise how developmental vessel regression is driven by cell migration, where cells are at- tracted to vessel segments that have higher organogenesis fate will contribute knowl- edge necessary to close the gap between basic model research and applied clinics.
The vascular biologist Holger Gerhardt, from common progenitors. Her findings on who joined the program in , identified blood flow, activily moving out of segments with poor flow. Genetic variability among chronic inflammation that is often shared ducted the first GWAS for the atopic march and showed that there are specific genetic individuals plays an important role in the development and progression of cardiovas- cular disease. Genetic and genomic studies in human populations are investigated by Young-Ae Lee to understand the etiology of by other forms of common human cardio- vascular and metabolic diseases.
The physiologi- cal functions of these systems are analyzed by the production and analysis of transgenic and gene-targeted animal models. Among the hormones studied, serotonin is of spe- cial interest, since it is not only involved in vascular homeostasis and other peripheral functions, but also serves as potent and multifunctional neurotransmitter in the brain. Renin-angiotensin system The renin-angiotensin system RAS is of central importance in blood pressure regu- lation and in the initiation of target organ damage.
In particular, local angiotensin-II generating systems in tissues such as brain, heart, vessels, and kidney are involved in these processes. Therefore, transgenic rats with local up- or downregulation of RAS components in these organs, e. Other genetically altered mouse and rat models for non-classical RAS components such as neurolysin, ACE2, the pro renin receptor, angiotensin and its receptor Mas, have elucidated the physi- ological function of these molecules.
More- over, a novel peptide of the RAS, alamandine, with its receptor, MrgD, was discovered and functionally analyzed. Furthermore, these animals showed that angiotensin and Mas are important for insulin sensitiv- ity and the pathogenesis of metabolic syn- rat model with inducible diabetes mellitus type 2 a novel oral formulation of angio- tensin was shown to exert potent an- tidiabetic actions revealing the therapeutic drome.
In a newly established transgenic potential of the protective RAS axis. In ad- served in ACE2-deficient mice. This may also be the reason for the blunted exercise-induced hippocampal neurogenesis which we ob- Kallikrein-kinin system and chemokines The kallikrein-kinin system KKS is an im- portant hormone system for cardiovascular regulation also mostly counteracting the effects of the RAS.
As models for the func- tional analysis of the KKS in intact animals, transgenic rats were generated expressing different components of the system, such as tissue kallikrein, the kinin B1 or the B2 receptor either ubiquitously or specifically in cardiovascular organs. These animals supported the protective role of the KKS in kidney and heart against ischemic, diabetic, and hypertrophic injury. Knockout mice for the kinin B1 receptor and mice lacking both kinin receptors were generated and revealed important functions of these pro- Moreover, kinin receptors turned out to be involved in arteriogenesis, sepsis, stroke, multiple sclerosis and high-fat diet induced obesity.
Moreover, downstream mediators of kinins teins in pain perception and inflammation. Mice deficient for angiotensin converting enzyme 2 ACE2 develop liver steatosis with age. Liver tissue sections of ACE-knockout lower panels and wildtype upper panels mice at 3 left and 6 months right of age were stained for adipophilin, which labels lipid droplets in the cells.
Mice with a local deletion of CXCL12 in ischemic damage. CXCL5 was characterized cardiomyocytes and transgenic rats over- expressing the chemokine in this cell type revealed an unexpected deteriorating role of this chemokine for heart function after as major determinant of macrophage foam cell formation in atherosclerosis.
Serotonin system Serotonin is a monoamine which func- tions as an important neurotransmitter in the central nervous system and as a major peripheral mediator produced by entero- chromaffin cells of the gut and transported TPH2. Mice deficient in TPH1, the isoform and released by platelets in the circulation. We discovered that vertebrates have two tryptophan hydroxylases, the rate limiting enzymes in serotonin synthesis, TPH1 and responsible for the synthesis of serotonin in the gut, showed that peripheral sero- tonin is involved in thrombosis, pulmonary hypertension, remodelling of mammary glands, tumor angiogenesis, liver regen- eration, and hepatitis, but not in bone me- tabolism as previously suggested.
Mice deficient in TPH2, the isoform responsible for the synthesis of serotonin in the brain, were surprisingly viable and fertile, despite a near complete lack of serotonin in the brain, and showed growth retardation and altered autonomic control leading to im- pairment of sleep, respiration, cardiovas- cular and metabolic parameters. We also revealed that exercise-induced adult neu- rogenesis is abolished in these animals.
In addition, TPH2-deletion is correlated with increased aggression, maternal neglect, and reduced aversive and anxiety-like behavior. Moreover, lack of TPH2 evoked increase in sexual activity of female mice. Since fur- ther behavior analysis of this model was hampered by poor ability of the mouse for complex social interactions and learning capacity, we now perform these studies in TPH2-deficient rats generated via zinc- finger-nuclease based gene-deletion Fig.
Since serotonin is a major determinant in the pathogenesis of several diseases, such as pulmonary hypertension, we developed and patented modulators of TPH activity as novel therapeutic drugs together with the high-throughput screening platform and the medicinal chemistry department of the Research Institute for Molecular Pharma- cology FMP and the Helmholtz Protein Sample Production Facility PSPF.
MDC Research Report 5. Rats deficient for tryptophan hydroxylase 2 TPH2 lack serotonin in the brain. Female KPNA2 deficient mice are infertile. Thus, KPNA2 is a maternal effect gene and a marker of zygotic genome activation. Identification of importin alpha 7 specific transport cargoes using a proteomic screening approach. Adverse left ventricular remodeling by glycoprotein nonmetastatic melanoma Klempin, F. Sero- tonin is required for exercise-induced adult hippocampal neurogenesis.
Cxcl5 limits macrophage foam cell formation in Huegel, S. Michael Bader Scientists Dr. Transgenic rats overexpressing the androgen receptor in cardiomyocytes exhibited marked altera- tions in cardiac rhythmicity probably due to dysregulation of potassium channels and mice lacking the receptor in macrophages revealed its function in salt homeostasis and blood pressure control. Importins Importins are essential components of the nucleus of eukaryotic cells. In a collabora- mice for five paralogs. The most obvious importin alpha1 and alpha7: The female infer- tility of importin alpha7 knockout mice is based on its essential function during zy- gotic genome activation of developing em- bryos.
For importin alpha1 the molecular basis is still under investigation Fig. Furthermore, importin al- portin paralogs. Transgenic and stem cell technology The group has also a strong emphasis in pha7 is involved in Influenza and Ebola vi- rus infection of cells. In parallel, proteomic specific import cargos of single alpha im- the field of rat embryology and stem cell in physiological and behavioural studies.
In fibroblasts upon infection with lentiviruses specific genes. The first target genes were tor. Furthermore, transgenic rats have been produced car- rying constructs, which express small in- terference RNAs suited to downregulate the insulin receptor, the pro renin recep- tor, apolipoprotein E, and the LDL recep- established and successfully used to ablate genes in rats. Modelling serves to test and formulate biological hy- potheses in a quantitative way as well as to predict the behavior of complex pathways and networks.
However, the timing of spikes within a cell is random because each interspike interval has a large onic kidney cells and rat primary hepa- tocytes, we also found that the average in- terspike interval varied between individual cells 1. The lines are single exponential functions fit to the experimental data. Frontiers in Physiology 6, J. Falcke, Formation of Transient Lamellipodia. PLoS one 9, e Greengard, P. Falcke, How does the ryanodine receptor in the ventricular myocyte wake up: European Biophysics Journal 41, 27 Sneyd, Models of Calcium Signalling. Chamakuri, A multiscale computa- tional model of spatially resolved calcium cycling in cardiac myocytes: Stephen Gilbert PhD students Setareh Dolati Janine Vierheller Behnam Amiri Nicolai Friedhoff Daniel Schwabe Graduate and Undergraduate students Wilhelm Neubert reliably encoded changes in stimulus in- tensity, and they resulted in an exponential dependence of average interspike interval on stimulation strength.
Mathematical modelling of excitation-con- traction coupling ECC in ventricular cardi- ac myocytes is a multiscale problem, and it tailed simulation tools. We developed a novel computational approach to resolve the concentration gra- dients from dyadic space to cell level by us- MDC Research Report 9. The ultimate goal of our research activities is to advance our understanding of mechanisms and mol- ecules controlling formation and pattern- ing of a hierarchically branched vascular network such that we can inform, innovate and implement therapeutic approaches to mitigate cardiovascular complications, and establish or restore tissue homeostasis in compromised patients.
We further use iteration between predictive computational modeling and experimentation to develop hypothesis and systems level understanding of the processes at play. Many projects in our team currently converge on investigating how endothelial cells collec- tively coordinate functional vessel remod- eling, i. We are also beginning to address the mechanisms regulating main- tenance and plasticity of vascular networks in adult physiology, and principles of func- tional adaptation, as well as maladaptation in vascular disease. The present report however will focus on and novel mechanism of lumen formation in angiogenesis and its implications for ves- sel plasticity.
Indeed, the earliest vascular lu- form in cell culture in the absence of flow, and blood flow are established, following a established fluorescent reporters for the segmental vessels of zebrafish embryos. By can form de novo through this mechanism. Most vascular networks in vertebrates how- ever form and extend after cardiac activity process known as sprouting angiogenesis, and lumen formation mechanisms in these conditions are not fully understood. We apical membrane i.
The cell division Charras and Paluch, Interestingly, by following the However, unlike classical blebs, the apical membrane deformations display an invert- ed polarity, with the membrane protruding dynamics of the actomyosin cytoskeleton during this process, we found that lumen expansion by inverse blebbing is tightly regulated through local and transient re- cruitment and contraction of actomyosin at the surface of the blebs, thus allowing controlled growth of new lumen branches.
Using inducible single-cell loss-of-function approaches, we identified that endothe- lial cells with impaired contractility fail to expand lumens or show dilated, multi- branched lumens. Together, these results unravel a novel mechanism of lumen for- mation in blood vessels, where a tight bal- ance between the pushing forces exerted by the blood on the membrane of endothelial cells and the endothelial cells own contrac- tile responses is required for shaping new vascular tubes Gebala et al, Future work will need to establish how this exqui- site elasticity of the apical membrane and its underlying actin cortex contractility is regulated during the angiogenic process, as vessels mature and are subjected to higher and changing levels of blood pressure.
Interestingly, the nascent lumen appears flow or increased endothelial contractility flow regimes in the course of physiological flow regulation. Thus mature lumens must lead to lumen collapse. This is in marked contrast to mature vascular networks, which experience changing pressure and somehow be stabilized, yet the mechanisms are unclear. Whereas nascent lumens can form within single endothelial cells or be- tween two cells, the mature endothelial through dynamic cell rearrangements that require regulated junctional VE-cadherin turnover Bentley et al, and junc- tional actin nucleation through the formin Fmnl3 Phng et al, Live imaging in configuration in capillaries shows generally lel junctional profiles run along the length of each vessel.
The configuration is achieved zebrafish embryos illustrated that Fmnl3 failed endothelial rearrangement. Instead localizes to endothelial junctions, and in- ducible endothelial expression of dominant negative Fmnl3 causes lumen collapse and of forming parallel junctions, endothelial cells lacking Fmnl3, or exposed to chemical fomin inhibitors, maintained isolated ring- like junctions.
Recent work by the team of Markus Affolter suggest that the c-terminal binding of actin to VE-cadherin is critical for junctional force transmission that drives en- dothelial cell shape changes and rearrange- ments during vessel elongation and lumen stabilization Sauteur et al How Fmnl3 activity and localization is regulated, and whether blood flow itself is involved in its recruitment to the junction remains to be shown.
Our future work will need to unravel the complexity and dy- namics of the junctional complexes at play during these morphogenic processes in development. From a clinical perspective, we will seek to establish whether and how endothelial reactivation in adult physiology or inflammation might destabilize vascular lumens and therefore contribute to small vessel disease. Nature cell Start of the Group: September Group Leader Prof.
Elena Cano Rincon Dr. Russell Thomas Collins Dr. Baptiste Claude Coxam Dr. Andre Sousa Rosa Dr. Anna Bozena Szymborska-Mell Dr. Note the distinct actin accumulation along endothelial junctions visible as thin lines running across and along the vessels. Nature cell biology Nature cell bi- way: Devel- opmental cell The group focuses on titin, the largest protein in the human body, and the multifunctional coxsackie- and adenovi- rus receptor CAR.
We utilize animal models and differentiated stem cells combined with cell biological, biochemical, genetic, pharma- cological, and omics tools to establish titin as a mechanosensor and study sarcomere dynamics. With a loss of function approach, we have demonstrated that CAR is crucial for embryonic development, determines the electrical properties of the heart, and can serve as a therapeutic target to improve cardiac remodeling. Currently our main trans- lational focus is on harnessing alternative splicing to improve cardiac function using a pharmacological screen with custom splice reporter assays.
This work aims to identify and characterize patients with splice related heart disease towards improved personalized diagnostics and therapy. Titin con- M-band to form a continuous filament. Using our animal models, we were able to which provide elastic diversity through alternative splicing and posttranslational Titin in sarcomere assembly and heart disease Titin is a giant protein found in vertebrate muscle, where it extends over the half-sar- comere and integrates into the Z-disc and and to link titin to adrenergic signal trans- duction, lateral growth of the sarcomere, and the hypertrophy response.
We study the role of titin in cardiac adaptation and how it converts mechanical input into a molecular signal. When we started the CAR conditional knockout project, the analysis of CAR in muscle and heart disease had been restrict- ed to basic expression and localization anal- ysis, which indicated an important role in remodeling after myocardial infarction.
Ac- cordingly, CAR expression is low in the adult but CAR is upregulated in areas surround- ing myocardial infarction. Our conditional knockout provided novel insights into the role of CAR in arrhythmia and established its role in myocarditis and myocardial in- farction.
We use cell- and animal models to understand the molecular and cellular basis of heart disease. Focusing on the sarcomeric protein titin and cardiac splicing, we integrate a candi- date- with a systems biology approach to derive splice regulatory networks and therapeutic targets. With high throughput screening to identify splice regulators and validation in cell and animal models, we aim to develop novel therapeutic strategies for cardiac disease. CAR effects the cytoskeleton, endocytosis, and signal transduction using inducible CAR deficient ES and iPS-cells, cardiomyo- our findings and develop biologicals to in- cytes, and neurons Figure 2.
We translate terfere with CAR function and improve the outcome of mice with myocardial infarction by improving the response to ischemia. CAR is a multifunctional protein. CAR light green is involved in cell contact formation, actin filament assembly, ion homeostasis gap junctions , endocytosis, and several signal transduction pathways.
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It interacts with multiple extra- and intracellular proteins. Regulation of cardiac function via alternative splicing. RBM20 is a cardiac splice factor that determines the elastic properties of the sarcomeric protein titin. Its substrate spec- trum is now well characterized and RBM20 has been linked to human cardiomyopathy with fibrosis, arrhythmia, and sudden death.
Alternative splicing and regula- tion of titin isoform expression in health and disease Alternative splicing has emerged as a major source of proteome diversity and as a cen- tral regulator of protein isoform expression in development and disease. In an integra- tive approach, we have used rodent and human genetics, cardiac physiology, and functional genomics to identify RBM20 as a novel trans- acting factor regulating the differential splicing across a broad range of transcripts during normal development Figure 3.
Notably, this is one of the few examples of a human disease mechanism involving an effect in trans. Our extended splicing analysis suggests that RBM20 tar- gets a subset of cardiac genes that concert- edly affect biomechanics, electrical activity, and signal transduction. This analysis of cardiac isoform expression does not only offer insights into the coordination of splic- ing events, but provides novel diagnostic and therapeutic targets for cardiac disease. B Titin fusion proteins are properly integrated into the sarcomere to produce the characteristic periodic Z-disc Red and M-band staining green.
EP A1 Polynucleotides for use in medicine. J Mol Med 94 The University of Klingel K, Gotthardt M. J Virol 1;88 J Clin Invest 8: J Cell Biol , Michael Gotthardt Scentists Dr. Recently, we have added a naturally occurring animal model to our portfolio that exhibits little muscle atrophy despite extended periods of im- mobilization — namely the hibernating griz- zly bear. Using an omics and mathematical modeling approach, we derived novel ther- apeutic targets to help prevent muscle atro- phy in aging, immobilization, and inherited muscle disease.
In a gain of function approach we engi- fluorescently labeled titin molecules that enable the analysis of titin mobility, sar- comere assembly, remodeling, and turn- over under different mechanical loads, in embryonic versus postnatal development, and in cardiac and skeletal muscle disease Figure 4. To evaluate compartmentalized mechanosignaling and follow changes in protein composition along the sarcomere in health and disease, we have now estab- lished localization proteomics in vivo us- already provided us with insights into sub- nuclear compartmentalization of splicing, ing the BioID system.
This approach has and now enables the quantification of pro- plasticity of myofilaments. This work complements our live imaging analysis of sarcomere assembly in titin GFP and RFP knockin mice towards understanding the We will build on our expertise in generating and analyzing animal models to study the molecular basis of cardiovascular, skeletal muscle and neurological disease, identify therapeutic targets, and to evaluate novel therapeutic strategies. This includes the E: Bio initiative of the BMBF for personalized di- agnostics and therapy of splice related car- diac disease as well as the FMP-screening and drug development infrastructure and outsourcing of the production of biologicals under GMP conditions.
Often such perturbations of biological networks, induced by complete knockout or over-expression of individual genes, have been used to help understand- ing the molecular basis of human diseases. Any layer of regula- tion can affect expression of a gene, and we are more and more interested to look not only at the genetic variation regulation of gene expression but also at effects in post- transcriptional and epigenetic processes of complex disease. We are interested in all levels of regulation in the rat and human. Genetic regulation on multiple layersWe are interested in the identification of genes and pathways that predict aberrant physiology in complex disease or meta- bolic control.
The spontaneously hyperten- sive rat SHR is the most widely studied animal model of human hypertension and it displays a large number of other physio- logical and pathophysiological phenotypes, including stroke, cardiac hypertrophy and failure, and features of the human meta- bolic syndrome. We constantly seek to improve our strategies and methods using deep re-sequencing and tion of key genetic regulators in the animal model.
The next step for us was to extend our studies to the regulation on the trans- lational level. Several genetic disorders are caused by mutations that affect protein translation, but so far genome-wide pro- tein synthesis rates have not been studied in complex disease models. Therefore, we adapted a new method, ribosome profiling RNA sequencing and ribosome profiling strain-specific translational regulation in ribosomes are captured and sequenced. In the spontaneously hypertensive rat.
With this technique, only the parts of mRNA molecules that are occupied by translating Ribo-seq , and performed genome-wide in heart and liver tissues to investigate our lab, we optimized this method to make 18 MDC Research Report QTLs are genetically variable loci that strongly link to transcription and translation differences.
We found hundreds of strain-specific differences in translation, the RI panel. We integrate these data with We extend this approach to liver and left-ventricular tissue of all 30 animals of panel-wide genotype information to per- form quantitative trait loci QTL mapping.
Using both transcriptional and translational information we can identify local cis and distant trans effectors of both levels of gene expression regulation and discriminate genetic loci regulating transcript abundance eQTLs from genetic loci acting purely at the translational level ferences on the transcriptional level tend to be equally apparent on the translational level.
Remarkably, Ribo-seq data also ex- riboQTLs.
We find that strain-specific dif- pose strain-specific differences in transla- tome level. They do influence final cellular lation influenced the expression levels of protein abundance, and almost double the number of differentially expressed genes between the strains. Translational regu- many genes with potential relevance to the cardio-metabolic disease phenotype of tion, which are invisible at the transcrip- the SHR rat, including the cardiac disease genes Myh6 and Fads1 and genes regulat- ing metabolite levels e. Moreover, several human GWAS candidates were found to be primarily translationally regulated in the rat model.
These data pro- vide insight in the wide variety of genetic mechanisms that introduce variation in gene expression levels, possibly contribut- ing to complex disease. Recently, we have adapted this technique to human left- ventricular biopsies of dilated cardiomy- opathy DCM patients. When the transcriptional level, we find many such as TBX The latter could be an indication of a regulatory function for these lncRNAs during translation or the differential translation of so far unknown micropeptides potentially playing a role in DCM. Combined, these data suggest a vari- ety of potential novel disease mechanisms driven by transcriptional and translational regulation in the human heart.
A In cis, a genetic variant may change specific transcript properties that affect translational efficiency. Figure 3 A The Endog gene is differentially transcribed and differentially translated. B An example of a gene Nop16 with transcriptional regulation in cis, this effect is absent at the translational level translational buffering. C The Myzap gene has no local regulator of transcription, but does have a local genetic variant strongly linked to a translational difference. In collabora- deficient in titin splicing and found a loss- tion with Michael Gotthardt MDC we used genome-wide approaches in a rat strain of-function mutation in RBM20 as the un- derlying cause for the pathological isoform expression of titin.
Mutations in RBM20 in humans have previously been shown to disrupt isoform transitions of a network of genes with essential cardiac functions and cause dilated cardiomyopathy. We showed human disease phenotype. We identified with high-throughput sequencing CLIP- seq experiments. The identification of di- splicing repressor in the heart.
Using SILAC directly RBM20 regulated transcripts by ap- plying state-of-the-art RNA-protein cross- linking and immunoprecipitation coupled based proteomics we demonstrated direct interaction with important spliceosomal components and showed how mutations within RBM20 may disrupt its repressor function. We further revealed that not only genetic variation, but also the modulation of RBM20 gene expression levels is opera- tive in the regulation of its network and may be an attractive target for therapeutic inter- vention. These binding data will be used to extend our studies determining the impact of genomic variability on posttranscrip- emphasize the importance of posttranscrip- tional regulation in cardiac function and provide novel mechanistic insights into the pathogenesis of human heart failure.
Our studies In addition to the identification of thousands pact on histone modifications in rat tissue. We quantified the genome-wide genes, respectively. As the exam- ined histone marks were known predictors of gene expression states, data on genetic variation underlying histone marks could genomic region was identified impacting significantly increase the number of eQTLs. Hence, we could show that genetic variation Selected Publications Angiogenesis. Nat Commun 7 Nat Genet 49, no.
Sci Transl Med 7, no. Nat Commun 6 J Clin Invest , no. Our focus is to understand the basic mechanism of transposition and the interplay between TEs and host cells in mammals. The Mobile DNA team inte- grates basic knowledge with technologies that are revolutionizing genomic manipula- tions in vertebrate species, including gene therapy, transgenesis, cancer research and functional genomics.
The impact of domesticated TE-derived sequences J. Raghunathan Occasionally transposons are co-opted for cellular functions. A high throughput pro- tein interaction screen identified cellular gest an important ramification for the pres- interacting partners of the Sleeping Beauty and piggyBac transposases. Our data sug- ence of domesticated piggyBac-like ele- ments in the human genome. Recent studies indicate that some families of ancient endogenous retroviruses ERVs , such as HERVH has a role in the acquisition and maintenance of pluripotency in pri- mates.
Using human pluripotent stem cells as models, we aim at deciphering the po- tential biological functions of TEs in human pluripotency see press release: LBP9 belongs to the CP2 family of transcription factors.
We study how the CP2 family is involved in the self-renewal and differentiation poten- tial in human pluripotent cells. We investigate the impact of conserved TEs during primate evolution collab. Transcriptional expres- sion of TEs is tightly controlled during de- velopment and seems to be deregulated in certain diseases. TEs have likely played a key role in distrib- uting non-coding, regulatory elements in the vertebrate genome. We investigate the potential impact of the evolutionary con- served Medium Reiterated frequency re- peats MERs. Anwar Transposon-host interaction S.
We investigate the noise, generated by various TEs is relatively certain TE families, including LINE-1 and risk of genetic destabilization inflicted by In comparison to other tissues, the genomic high in placenta. In collaboration with Our upregulation of human endogenous TEs in cancer. TEs are best described as molecular para- sites with the potential to give rise to a variety of genetic alterations. Such altera- tions include mutational damage to gene function, but can also provide useful ge- netic variability in host genomes. Thus, in contrast to most viruses, TEs and the host have coevolved in a way that permits prop- agation of the transposon, but minimizes damage to the host.
TEs make several inter- actions to host cellular machineries, piggy- back and modify certain basic mechanisms of the host organism. Our studies indicate that transposition is sensitive to stress, and stress-response involves a complex, inter- active regulatory platform involving evolu- tionary conserved cellular mechanisms. Thus, transposons might exist in to sense developmental and environmental changes and manipulate stress signalling. Translating experience accumulat- ed in TE research to cutting-edge technologies H. Klinge TE-based, non-viral integrating vector sys- tems represent a novel technology that opens up new possibilities for gene thera- py.
The SBX system provides long-term expression in various primary and stem cells. As an im- portant issue regarding the implementa- tion of clinical trials, transposon vectors can be maintained and propagated as plas- mid DNA, making them simple and inex- pensive to manufacture e. In order to fill the gap between the recent serious issue; 2 try the SB system in dis- vector development and clinical trials we 1 try the SB system in disease models that were already on clinical trials using retroviral vectors, but where safety was a ease models that were already on clinical trials using retroviral vectors, but feasibil- MDC Research Report Regulated complex assembly safe- guards the fidelity of Sleeping Beauty transposition.
Isola- expression Nature Protocols Feb;11 2: Epub Jan Germline trans- Nature Prot. Hospi- transposon-based regenerative technol- ogy has a potential — cell-based pacemaker [collaboration M. Spuler ECRC see press release: A great advantage of the ditions avoiding chemical fixation and limi- We develop the SB as a novel tool for chro- matin 3D mapping. The SB transposon is suitable for somatic mutagenesis and emerged as a powerful tool in cancer research. We utilize SB in a rat model to decipher gene regulatory net- works cooperating in hormone- dependent breast cancer development, progression and metastasis collab.
Bader MDC , D. Transposons can be harnessed as vehicles for introducing mutations into genes. By combining transposon mutagenesis with the innate potency of spermatogonia, com- prehensive libraries of gene knockouts are used to study fertility and behaviour col- lab. We use hiPSCs and genome engineering in a Kcnq1 model of type 2 diabetes aiming drug screening. In the cardiovascular system, cAMP, for example modulates contractility of cardiac myocytes and participates in the control of blood pressure through vascular smooth muscle cells.
How- ever, this does not occur due to its degrada- tion by cyclic nucleotide phosphodiesterases PDEs.
PDEs are constitutively active enzymes that are located in compartments, and thus establish gradients of cyclic nucleotides. PKA holoenzyme consists of a dimer of regulatory R subunits and two catalytic C subunits. PKA directly interacts with A-kinase anchoring proteins AKAPs , a family of around 50 scaf- folding proteins, that tether the enzyme to 26 its substrates.
Phosphatases dephosphory- late target proteins, counteracting PKA activ- ity. AKAPs possess specific protein interaction that facilitate specific cellular responses to specific extracellular cues figure 1. PDE3A1, A2 and A3 all contain the same catalytic region and are similar concern- ing catalytic activity and inhibitor sensitivity.
Movsesian, University of laboration with the groups of V. The mutations are adjacent to each other and responsible for amino acid substitutions in a conserved region that is present in PDE3A1 and PDE3A2 and to which a function has not been ascribed, but which is in close proximity to the catalytic domain. Together with increased constriction this is likely causative for the increased peripheral vascular resistance in the patients and ex- plains the hypertensive phenotype.
In order to gain insight into the physiological function of GSKIP we gen- is involved in the regulation of different bio- logical processes, including embryonic de- velopment, cell cycle progression, glycogen metabolism and immune regulation. Deregu- such as cancer or cardiac hypertrophy. The prevalence of allergic diseases has increased to epidemic dimensions over the past decades. We complement clinical pheno- types with precise molecular phenotypes to characterize underlying functional path- ways.
Chronic inflammation has become one of Regardless of the mechanism of inflamma- tion, inappropriate inflammatory responses to environmental, microbial or self antigens contribute to dysfunction and destruction of target organs. Epidemiologic data pro- matory conditions that have previously been thought to be unrelated. Our recent studies highlight the genetic overlap between risk loci for allergic dis- inflammatory disorders in industrialized influence immune response thresholds to favor chronic inflammatory disease in the ease with those for other chronic inflam- 95, controls identified 10 novel loci ceptibility loci to 31 1.
While activation and specification. In summary, the importance of the skin barrier defect and of an exaggerated immune response to environmental allergens in eczema is well established, all new susceptibility loci were related to auto- immune regulation, in particular innate signaling and T-cell ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis, or type 1 diabetes, pointing to common mechanisms involved in eczema and other immune-mediated traits.
Molecular pathways involved in in- nate immune signaling and T-cell polar- our results suggest that targeted immune modulation could be another promising ap- proach for the treatment of eczema. We analyzed the genetic determinants underlying disease progression from eczema to asthma. Over the years, we have recruit- many cases, we have obtained prospective clinical data of the of allergic disease course and sensitization patterns.
Recently, we used the longterm clinical ed several thousand study participants. In data to perform the first genome-wide analysis of allergic disease prognosis.
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While four of them, FLG 1q We showed that having a FLG carrier mother increased the eczema risk of the child even when the mutations were not transmitted. The FLG ma- ternal effect was observed only when mothers had allergic sensitization, suggesting that FLG mutation-induced systemic immune responses in the mother may influence eczema risk in the child.
Parent-of-origin effects Epidemiological studies on allergic dis- eases have shown that maternal allergy is a stronger risk factor for the child than pater- nal allergy. The molecular basis of this pref- erential maternal transmission of allergy risk is currently unknown but it can poten- tially occur through two different biologi- cal mechanisms: In genomic imprinting, either the maternally or the pa- ternally inherited allele is expressed and the other allele is silenced.
Thus, the effect of an allele depends on parental origin re- sulting in phenotypic differences between reciprocal heterozygotes parent-of origin effects. Alternatively, maternal genotype effects occur when the maternal genotype genotype and occurs through the maternal- ly provided environment during prenatal development. We analyzed the four most prevalent European FLG mutations in complete nuclear families with eczema from Central Europe. For the analysis, we strongest genetic risk factors for eczema which has been involved in ciliary dysfunc- tion in brain and lung providing a potential link to asthma.
The second novel locus in- cluded the solute carrier family 6, member 15 gene SLC6A Selective inhibition of SLC6A15 by the histamine H1 receptor an- tagonist loratadine which is clinically used for the treatment of allergic disease, was recently reported. Support- eczema loci were found to be associated risk for the atopic march without any effects on eczema alone or asthma alone.
This finding highlights that induce chronic inflammation and may the role of the skin as the interface between host and environment in shaping not only local, but also systemic immune responses Our results suggest that genes triggering eczema are the main genetic determinants affect distant organs in the host. A causal relationship between eczema and this asth- ma subtype has important implications for interventional strategies.
Since no cure for asthma exists, the modulation of skin im- mune homeostasis early in infancy could be an effective strategy to prevent not only eczema but also the disease progression along the atopic march. Indel eQTLs splice sites. Interestingly, a substantial pro- were even more enriched in these regions suggesting that indels are more likely to be functional because they have a more del- eterious effect on regulatory elements and portion of SNPs previously found in GWAS on disease traits were correlated with in- dels with larger effects on eQTLs, support- ing the hypothesis that indels are more likely to be causal.
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Selected Publications Nature Genetics epub ahead of print. PLoS Genet 11, e Meta-analysis identifies seven susceptibility loci involved in the atopic march. Nat Commun 6, Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J Clin Invest , Young-Ae Lee Scientists Dr.