12 results on '"Görlach, Agnes"'
Search Results
2. Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy
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Spielmann, Nadine, Miller, Gregor, Oprea, Tudor I., Hsu, Chih-Wei, Fobo, Gisela, Frishman, Goar, Montrone, Corinna, Haseli Mashhadi, Hamed, Mason, Jeremy, Munoz Fuentes, Violeta, Leuchtenberger, Stefanie, Ruepp, Andreas, Wagner, Matias, Westphal, Dominik S., Wolf, Cordula, Görlach, Agnes, Sanz-Moreno, Adrián, Cho, Yi-Li, Teperino, Raffaele, Brandmaier, Stefan, Sharma, Sapna, Galter, Isabella Rikarda, Östereicher, Manuela A., Zapf, Lilly, Mayer-Kuckuk, Philipp, Rozman, Jan, Teboul, Lydia, Bunton-Stasyshyn, Rosie K. A., Cater, Heather, Stewart, Michelle, Christou, Skevoulla, Westerberg, Henrik, Willett, Amelia M., Wotton, Janine M., Roper, Willson B., Christiansen, Audrey E., Ward, Christopher S., Heaney, Jason D., Reynolds, Corey L., Prochazka, Jan, Bower, Lynette, Clary, David, Selloum, Mohammed, Bou About, Ghina, Wendling, Olivia, Jacobs, Hugues, Leblanc, Sophie, Meziane, Hamid, Sorg, Tania, Audain, Enrique, Gilly, Arthur, Rayner, Nigel W., Hitz, Marc-Phillip, Zeggini, Eleftheria, Wolf, Eckhard, Sedlacek, Radislav, Murray, Steven A., Svenson, Karen L., Braun, Robert E., White, Jaqueline K., Kelsey, Lois, Gao, Xiang, Shiroishi, Toshihiko, Xu, Ying, Seong, Je Kyung, Mammano, Fabio, Tocchini-Valentini, Glauco P., Beaudet, Arthur L., Meehan, Terrence F., Parkinson, Helen, Smedley, Damian, Mallon, Ann-Marie, Wells, Sara E., Grallert, Harald, Wurst, Wolfgang, Marschall, Susan, Fuchs, Helmut, Brown, Steve D. M., Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Herault, Yann, Lloyd, K. C. Kent, Dickinson, Mary E., Gailus-Durner, Valerie, and Hrabe de Angelis, Martin
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- 2022
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3. MondoA drives malignancy in B-ALL through enhanced adaptation to metabolic stress
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Sipol, Alexandra, Hameister, Erik, Xue, Busheng, Hofstetter, Julia, Barenboim, Maxim, Öllinger, Rupert, Jain, Gaurav, Prexler, Carolin, Rubio, Rebeca Alba, Baldauf, Michaela C., Franchina, Davide G., Petry, Andreas, Schmäh, Juliane, Thiel, Uwe, Görlach, Agnes, Cario, Gunnar, Brenner, Dirk, Richter, Günther H.S., Grünewald, Thomas G.P., Rad, Roland, Wolf, Elmar, Ruland, Jürgen, Sorensen, Poul H., and Burdach, Stefan E.G.
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- 2022
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4. Publisher Correction: Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy
- Author
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Spielmann, Nadine, Miller, Gregor, Oprea, Tudor I., Hsu, Chih-Wei, Fobo, Gisela, Frishman, Goar, Montrone, Corinna, Haseli Mashhadi, Hamed, Mason, Jeremy, Munoz Fuentes, Violeta, Leuchtenberger, Stefanie, Ruepp, Andreas, Wagner, Matias, Westphal, Dominik S., Wolf, Cordula, Görlach, Agnes, Sanz-Moreno, Adrián, Cho, Yi-Li, Teperino, Raffaele, Brandmaier, Stefan, Sharma, Sapna, Galter, Isabella Rikarda, Östereicher, Manuela A., Zapf, Lilly, Mayer-Kuckuk, Philipp, Rozman, Jan, Teboul, Lydia, Bunton-Stasyshyn, Rosie K. A., Cater, Heather, Stewart, Michelle, Christou, Skevoulla, Westerberg, Henrik, Willett, Amelia M., Wotton, Janine M., Roper, Willson B., Christiansen, Audrey E., Ward, Christopher S., Heaney, Jason D., Reynolds, Corey L., Prochazka, Jan, Bower, Lynette, Clary, David, Selloum, Mohammed, Bou About, Ghina, Wendling, Olivia, Jacobs, Hugues, Leblanc, Sophie, Meziane, Hamid, Sorg, Tania, Audain, Enrique, Gilly, Arthur, Rayner, Nigel W., Hitz, Marc-Phillip, Zeggini, Eleftheria, Wolf, Eckhard, Sedlacek, Radislav, Murray, Steven A., Svenson, Karen L., Braun, Robert E., White, Jaqueline K., Kelsey, Lois, Gao, Xiang, Shiroishi, Toshihiko, Xu, Ying, Seong, Je Kyung, Mammano, Fabio, Tocchini-Valentini, Glauco P., Beaudet, Arthur L., Meehan, Terrence F., Parkinson, Helen, Smedley, Damian, Mallon, Ann-Marie, Wells, Sara E., Grallert, Harald, Wurst, Wolfgang, Marschall, Susan, Fuchs, Helmut, Brown, Steve D. M., Flenniken, Ann M., Nutter, Lauryl M. J., McKerlie, Colin, Herault, Yann, Lloyd, K. C. Kent, Dickinson, Mary E., Gailus-Durner, Valerie, and Hrabe de Angelis, Martin
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- 2022
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5. Compound Mutation in Cardiac Sarcomere Proteins Is Associated with Increased Risk for Major Arrhythmic Events in Pediatric Onset Hypertrophic Cardiomyopathy.
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Pollmann, Kathrin, Kaltenecker, Emanuel, Schleihauf, Julia, Ewert, Peter, Görlach, Agnes, and Wolf, Cordula M.
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HYPERTROPHIC cardiomyopathy ,CARDIOMYOPATHIES ,CARDIAC arrest ,EXERCISE tests ,CARDIAC magnetic resonance imaging ,VENTRICULAR arrhythmia ,GENETIC testing - Abstract
Hypertrophic cardiomyopathy (HCM) is associated with adverse left ventricular (LV) remodeling causing dysfunction and malignant arrhythmias. Severely affected patients present with disease onset during childhood and sudden cardiac death risk (SCD) stratification is of the highest importance in this cohort. This study aimed to investigate genotype–phenotype association regarding clinical outcome and disease progression in pediatric onset HCM. Medical charts from forty-nine patients with pediatric HCM who had undergone genetic testing were reviewed for retrospective analysis. Demographic, clinical, transthoracic echocardiographic, electrocardiographic, long-term electrocardiogram, cardiopulmonary exercise test, cardiac magnetic resonance, and medication data were recorded. Childhood onset HCM was diagnosed in 29 males and 20 females. Median age at last follow-up was 18.7 years (range 2.6–51.7 years) with a median follow-up time since diagnosis of 8.5 years (range 0.2–38.0 years). Comparison of patients carrying mutations in distinct genes and comparison of genotype-negative with genotype-positive individuals, revealed no differences in functional classification, LV morphology, hypertrophy, systolic and diastolic function, fibrosis and cardiac medication. Patients with compound mutations had a significantly higher risk for major arrhythmic events than a single-mutation carrier. No association between affected genes and disease severity or progression was identified in this cohort. [ABSTRACT FROM AUTHOR]
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- 2021
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6. Funktionsanalyse von induzierten pluripotenten Stammzellen abgeleiteten Kardiomyozyten bei Patienten mit hypoplastischem Linksherzsyndrom
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Zhang, Zhong, Krane, Markus (Prof. Dr.), and Görlach, Agnes (Prof. Dr.)
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Medizin und Gesundheit ,ddc:610 - Abstract
Background: Hypoplastic left heart syndrome (HLHS) is a severe genetically heterogeneous congenital heart disease that encompasses several pathophysiologies. The genetic mechanism of HLHS is still unclear, and there is a lack of animal models to study the development of hypoplastic left heart structure。 Objective: The aim of this project is the comprehensive characterization of induced pluripotent stem cell (iPSC) lines derived from patients with HLHS and healthy controls and the production of highly enriched and pure cardiomyocytes (CMs). Methods: Before starting this thesis, iPSC lines were established from HLHS patients (n=3) and healthy controls (n=3) by integration-free transduction with Sendai virus. iPSC characterization included Sendai footprinting, the detection of endogenous pluripotency factor gene expression, and the capacity of iPSCs to differentiate were detected in cells of all three germlayers. A direct cardiac differentiation protocol with “small molecules” was applied to obtain high quality CMs. The iPSC-CMs were harvested on day 14 for analysis of gene expression, quality, and purity. Results: All iPSC lines were Sendai-virus free after 4 to 12 passages. Endogenous pluripotency factor expression could be detected in all iPSC lines, while expression of the reprogramming factor c-MYC was absent in two control lines. Direct cardiac differentiation showed the sensitivity of iPSC lines to CHIR99021 is quite variable. Furthermore, the initial cell seeding density could affect the efficiency of differentiation. The transcription factor TBX5 and its direct target gene NPPA were low expressed in the HLHS group, while expression of NKX2.5 was retarded until day 8 in the HLHS group but caught up by day 10. The expression of ISL1 and TNNT2 was similar in the two groups. iPSC-CMs started spontaneously beating between day 7 and 9. By day 14 more than 60% Trop T+ CMs could be detected in both the HLHS and control group. Conclusion: I have performed a complete characterization of six iPSC lines and determined defined and repeatable conditions for the production of iPSC-CMs of high quality and in large quantities. My results confirm that these iPSC lines are a powerful cellular system to study the molecular dysfunction of HLHS in vitro and the results confirm that iPSC-CMs can successfully be used in downstream applications such as the generation of engineered heart tissues. Hintergrund: Das Hypoplastische Linksherzsyndrom (HLHS) ist eine schwere, genetisch heterogene congenitale Herzerkrankung, die verschiedene Krankheitsbilder umfasst. Die genetischen Ursachen des HLHS sind noch immer unklar und es gibt keine Tiermodelle, um die Entwicklung hypoplastischer Linksherzstrukturen zu untersuchen. Zielsetzung: Das Ziel dieser Arbeit ist die umfassende Charakterisierung induzierter pluripotenter Stammzell-Linien (iPS Linien), die von Patienten mit HLHS oder gesunden Probanden etabliert wurden und die Generierung von hoch angereicherten, reinen Kardiomyozyten (KMs). Methoden: Vor Beginn dieser Doktorarbeit wurden iPS Linien von HLHS Patienten (n=3) und gesunden Probanden (n=3) durch integrationsfreie Transduktion mit Sendaiviren etabliert. Die Charakterisierung der iPS Linien umfasste ein Sendai footprinting, den Nachweis der endogenen Expression der Pluripotenzfaktoren und die Untersuchung der Fähigkeit der iPS Zellen, sich in Zellen aller drei Keimblätter zu entwickeln. Um KMs von hoher Qualität zu erhalten wurde ein direktes kardiales Differenzierungsprotokoll mit „small molecules“ verwendet. Am Tag 14 der Differenzierung wurde die Genexpression, die Qualität und die Reinheit der aus den iPS Zellen generierten KMs analysiert. Ergebnisse: Nach 4 bis 12 Passagen waren alle iPS Linien frei von Sendai-Virus. Die endogene Expression der Pluripotenzfaktoren konnte in allen iPS Linien nachgewiesen werden, während in zwei Kontroll iPS Linien keine Expression des Reprogrammierungsfaktors c-MYC gezeigt werden konnte. Bei der direkten kardialen Differenzierung war die Sensitivität der iPS Linien gegenüber CHIR99021 sehr variabel. Darüber hinaus hatte die ursprüngliche Dichte der Zellen beim Aussäen einen Effekt auf die Effizienz für Differenzierung. Während dieser wurden der Transkriptionsfaktor TBX5 und NPPA, ein direktes Zielgen, in der HLHS Gruppe in sehr geringem Ausmass exprimiert. Die Expression von NKX2.5 war bis Tag 8 in der HLHS Gruppe verzögert, pendelte sich aber am Tag 10 ein. Die Expression von ISL1 und TNNT2 war in beiden Gruppen sehr ähnlich. Aus iPS Zellen generierte KMs begannen spontan zwischen Tag 7 und 9 zu schlagen. An Tag 14 konnten sowohl in der HLHS als auch in der Kontroll-Gruppe über 60% Trop T+ Zellen detektiert werden. Schlussfolgerung: In der vorliegenden Arbeit habe ich bei sechs iPS Linien eine komplette Charakterisierung durchgeführt. Ich habe definierte und reproduzierbare Bedingungen bestimmt unter denen KMs in hoher Qualität und in grossen Mengen aus iPS Zellen generiert werden können. Meine Ergebnisse belegen, dass diese iPS Linien ein leistungsfähiges zelluläres System darstellen, um die molekularen Dysfunktionen des HLHS in vitro zu untersuchen. Die Ergebnisse zeigen auch, dass die aus iPS Zellen generierten KMs in Downstream-Anwendungen wie etwa der Generierung von engineered heart tissues verwendet werden können.
- Published
- 2023
7. Ein gezielter Eingriff in den Krebsstoffwechsel erhöht die Radiosensitivität durch Beeinträchtigung der Hitzeschockreaktion
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Schwab, Melissa Elisabeth, Multhoff, Gabriele (Prof. Dr.), Görlach, Agnes (Prof. Dr.), and Gaipl, Udo (Prof. Dr.)
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lactate metabolism, radiosensitivity, Hsp70, stress response, LDHA/B double knockout ,Biowissenschaften, Biologie ,ddc:570 ,Laktatstoffwechsel, Radiosensitivität, Hsp70, Stressantwort, LDHA/B double knockout - Abstract
Increased lactate dehydrogenase (LDH) activity, elevated levels of lactate in the tumor microenvironment and overexpression of heat shock proteins can mediate radioresistance of cancer cells. In this study, I aimed to investigate the relationship of LDH and the cellular stress response with respect to radiation resistance. My results showed that the lactate metabolism and heat shock response are co-regulated in two different tumor cell systems and as a functional consequence the radiosensitivity of cancer cells was significantly enhanced by inhibiting lactate metabolism. Strahlenresistenz von Krebszellen kann durch eine erhöhte Laktatdehydrogenase Aktivität, erhöhte Laktat Konzentrationen und eine Überexpression von Hitzeschockproteinen verursacht werden. In meiner Promotion untersuchte ich, inwieweit Strahlenresistenz durch einen Eingriff in den Laktatmetabolismus der Krebszellen überwunden werden kann. Meine Daten zeigten, dass der Laktatstoffwechsel und die Stressantwort in Tumorzellen co-reguliert werden und dass als Konsequenz die Strahlensensitivität von Krebszellen durch Hemmung des Laktatstoffwechsels erhöht wurde.
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- 2023
8. Pleiotrope Rolle des myozytären Zellzyklus bei angeborenen Herzkrankheiten
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Rawat, Hilansi, Moretti, Alessandra (Prof. Dr.), Klymiuk, Nikolai (Prof. Dr.), and Görlach, Agnes (Prof. Dr.)
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Congenital heart disease, human induced pluripotent stem cells, cell cycle, cardiomyocytes, Noonan syndrome, Hypoplastic left heart syndrome ,Naturwissenschaften ,ddc:500 ,Kongenitale Herzerkrankung, induzierte pluripotente Stammzellen, Zellzyklus, Kardiomyozyten, Noonan-Syndrom, Hypoplastisches Linksherzsyndrom - Abstract
Congenital heart diseases (CHDs) are the most common type of birth defect and the leading cause of pediatric mortality worldwide. We used 2D and 3D hiPSCs-based cardiac models and native patient samples to investigate CHDs, currently with limited treatment options, and identified cell cycle defects as a potential disease driver in Noonan syndrome (NS-CM) and Hypoplastic left heart syndrome (HLHS). Kongenitale Herzerkrankung (KHK) sind die häufigste Form von Geburtsfehlern und weltweit die Hauptursache für die Sterblichkeit von Kindern. Wir haben 2D- und 3D-hiPSC-basierte Herzmodelle und native Patientenproben verwendet, um KHKs zu untersuchen, für die es derzeit nur begrenzte Behandlungsmöglichkeiten gibt und haben Zellzyklusdefekte als potenziellen Krankheitstreiber beim Noonan Syndrom (NS-CM) und Hypoplastischen Linksherzsyndrom (HLHS) identifiziert.
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- 2022
9. Die Rolle der essenziellen NADPH Oxidase Untereinheit p22phox und reaktiver Sauerstoffspezies in der Pathogenese von Hypoxie-induzierter Pulmonaler Hypertonie
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Trautz, Benjamin Siegfried, Görlach, Agnes (Prof. Dr.), and Sager, Hendrik (Prof. Dr.)
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Medizin und Gesundheit ,ddc:610 - Abstract
Pulmonary hypertension (PH) is a progressive disease with no curative treatment so far, characterized by pulmonary vascular remodelling, elevated pulmonary arterial pressure and right ventricular hypertrophy. Since reactive oxygen species (ROS) might contribute to PH, the role of NADPH oxidases in the pathogenesis of PH was analysed. We found that loss of the NADPH oxidase subunit p22phox protected mice against the development of hypoxia-induced PH. Da reaktive Sauerstoffspezies (ROS) eine Rolle bei PH spielen könnten, wurde der Einfluss der NADPH Oxidasen in der Pathogenese der PH untersucht. Es konnte gezeigt werden, dass der Verlust der NADPH Oxidase Untereinheit p22phox vor der Entwicklung von Hypoxie-induzierter PH in der Maus schützte. Dies könnte ein Ansatz für neue Therapien sein.
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- 2021
10. Bewertung des Endothels bei der Entstehung von Neoatherosklerose in einem atherosklerotischen Kaninchenmodell und in humanen Zelllinien
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Stöger, Magdalena Annemarie, Joner, Michael (Prof. Dr.), and Görlach, Agnes (Prof. Dr.)
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Medizin und Gesundheit ,ddc:610 - Abstract
Neoatherosclerosis is the manifestation of atherosclerosis in the area of implanted coronary stents. The exact mechanism of its formation is not known yet. A delay in the formation of a protective endothelial layer, which is found on the stents surface after its implantation, probably plays a crucial role in the development of neoatherosclerosis. In this work, the endothelialization of various coronary stents was evaluated in order to gain insight into the pathogenesis of this disease. Neoatherosklerose ist die Manifestation von Atherosklerose im Bereich von Koronarstents. Der genaue Entstehungmechanismus ist noch nicht bekannt. Verzögerung der Ausbildung einer schützenden Endothelschicht, die sich nach Implantation von Stents auf deren Oberfläche findet, spielt vermutlich eine Rolle bei der Entstehung der Neoatherosklerose. In dieser Arbeit wurde die Endothelialisierung über verschiedenen Stents evaluiert, um einen Einblick in die Pathogenese dieser Erkrankung zu gewinnen.
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- 2021
11. Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome.
- Author
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Meier AB, Raj Murthi S, Rawat H, Toepfer CN, Santamaria G, Schmid M, Mastantuono E, Schwarzmayr T, Berutti R, Cleuziou J, Ewert P, Görlach A, Klingel K, Laugwitz KL, Seidman CE, Seidman JG, Moretti A, and Wolf CM
- Abstract
Childhood-onset myocardial hypertrophy and cardiomyopathic changes are associated with significant morbidity and mortality in early life, particularly in patients with Noonan syndrome, a multisystemic genetic disorder caused by autosomal dominant mutations in genes of the Ras-MAPK pathway. Although the cardiomyopathy associated with Noonan syndrome (NS-CM) shares certain cardiac features with the hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM), such as pathological myocardial remodeling, ventricular dysfunction, and increased risk for malignant arrhythmias, the clinical course of NS-CM significantly differs from HCM. This suggests a distinct pathophysiology that remains to be elucidated. Here, through analysis of sarcomeric myosin conformational states, histopathology, and gene expression in left ventricular myocardial tissue from NS-CM, HCM, and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11
N308S/+ induced pluripotent stem cells, we demonstrate distinct disease phenotypes between NS-CM and HCM and uncover cell cycle defects as a potential driver of NS-CM., Competing Interests: Dr. Wolf is a consultant for Day One Therapeutics. All other authors declare no competing interests., (© 2021 The Authors.)- Published
- 2021
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12. Molecular signaling pathways in right ventricular impairment of adult patients after tetralogy of Fallot repair.
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Pollmann K, Raj Murthi S, Kračun D, Schwarzmayr T, Petry A, Cleuziou J, Hörer J, Klop M, Ewert P, Görlach A, and Wolf CM
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Background: Right ventricular impairment (RVI) secondary to altered hemodynamics contributes to morbidity and mortality in adult patients after tetralogy of Fallot (TOF) repair. The goal of this study was to describe signaling pathways contributing to right ventricular (RV) remodeling by analyzing over lifetime alterations of RV gene expression in affected patients., Methods: RV tissue was collected at the time of cardiac surgery in 13 patients with a diagnosis of TOF. RNA was isolated and whole transcriptome sequencing was performed. Gene profiles were compared between a group of 6 adults with signs of RVI undergoing right ventricle to pulmonary artery conduit surgery and a group of 7 infants, undergoing TOF correction. Definition of RVI in adult patients was based on clinical symptoms, evidence of RV hypertrophy, dilation, dysfunction or elevated pressure on echocardiographic, cardiovascular magnetic resonance, or catheterization evaluation., Results: Median age was 34 years in RVI patients and 5 months in infants. Based on P adjusted value <0.01, RNA sequencing of RV specimens identified a total of 3,010 differentially expressed genes in adult patients with TOF and RVI as compared to infant patients with TOF. Gene Ontology and Kyoto Encyclopedia of Genes databases highlighted pathways involved in cellular metabolism, cell-cell communication, cell cycling and cellular contractility to be dysregulated in adults with corrected TOF and chronic RVI., Conclusions: RV transcriptome profiling in adult patients with RVI after TOF repair allows identification of signaling pathways, contributing to pathologic RV remodeling and helps in the discovery of biomarkers for disease progression and of new therapeutic targets., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-894). The series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part IV” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)
- Published
- 2021
- Full Text
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