September 2018 In an effort to support young scientists, Joachim Herz Stiftung awards fellowships amounting to 12,500 euros to outstanding interdisciplinary research projects for a period of two years. IMTTS researcher Ankita Garg (photo on the right) was awarded the prestigious “Add-On Fellowship for Interdisciplinary Life Science” for her work on understanding the miRNA based regulation of Mineralocorticoid receptor. With this fellowship, she will be able to explore the novel discipline of Engineered-heart tissues to better understand the effects of our regulatory microRNAs in cardiac disease settings.
September 2018 ERA-CVD is a funding organization which is a part of ERA-NET (European Research Area Network) with focus on cardiovascular diseases. This year an Excellent Paper was selected for the Cardiovascular Research Award (EPCA) with the idea to identify excellent work in the field of cardiovascular sciences and to promote young scientists. This year the publication of Dr. Shashi Kumar Gupta from the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) heady by Prof. Thomas Thum entitled "Quaking inhibits Doxorubicin-mediated cardiotoxicity through regulation of cardiac circular RNA expression" published in Circulation Research was selected for the award. The award was presented to Dr. Gupta at ESC-Congress 2018, Munich together with an ESC TV interview.
August 2018 The Institute of Molecular and Translational Therapeutic Strategies (IMTTS), directed by Prof. Dr. Dr. Thomas Thum, has joined the COST Action CA17129 „Catalysing transcriptomics research in cardiovascular disease (CardioRNA)“. Prof. Thum has been nominated as Substitute Member of the Management Committee on behalf of Germany. COST (European Cooperation in Science and Technology) actions are a European instrument to support cross-linking of national research activities on the European level. COST actions do not support individual research projects but rather networking activities, like congresses and exchange of scientists. The main aim and objective of the COST Action CardioRNA is to accelerate the understanding of transcriptomics in cardiovascular disease and further the translation of experimental data into practical applications for diagnostics and therapies. The COST Action will be implemented for a period of four years, starting upon the first meeting of the Management Committee in October 2018.
April 2018 Dr. Shashi Kumar Gupta from IMTTS received 2nd prize of Publikationspreis der Arbeitsgruppe Chronische Herzinsuffizienz at German Cardiac Society Meeting 2018 held in Mannheim. Prize was awarded for his publication titled “Quaking Inhibits Doxorubicin-Mediated Cardiotoxicity Through Regulation of Cardiac Circular RNA Expression” published in Circulation Research. Publication highlights the protective role of Quaking in preventing doxorubicin-induced cardiotoxicity.
March 2018 IMTTS-researcher Dr. Katharina Schimmel was awarded the runner-up in the Young Investigator Award session of the Dutch German Cardiology Meeting on March 16th in Amsterdam with her talk entitled “Natural compounds for the prevention and treatment of cardiac fibrosis and diastolic dysfunction”. Katharina had already presented her work in the Best Poster Session of the ESC congress 2017 in Barcelona further highlighting the relevance of her research.
March 2018 As participants in the annual retreat for the Hannover Biomedical Research School (HBRS) molecular medicine programme, IMTTS researchers Ankita Garg and Michael Dodsworth both received awards for best poster presentation and best oral presentation respectively. Ankita presented her work characterising mineralocorticoid receptor induced cardiac remodeling, whilst Michael introduced his PhD project on the role of circRNAs in hypertrophic cardiomyopathy induced heart failure. Both achievements highlight the importance and relevance of their work in the wider scientific field.
November 2017 IMTTS researcher Dr. Jan Fiedler has graduated in the interdisciplinary program TRAIN (translational alliance in Lower Saxony) academy. This intensive 2 years program included different modules aiming to understand the finding, development and clinical application of novel drug targets. Within the network of TRAIN academy, IMTTS has become a solid partner contributing in drug discovery research.
November 2017 IMTTS researcher Dr. Shashi Kumar Gupta was awarded with “Hans Heinrich Niemann Prize” from Gesellschaft der Freunde der Medizinischen Hochschule Hannover e.V. for his publication entitled “Pre-clinical development of a MicroRNA-based therapy for elderly patients with myocardial infarction” in the Journal of The American College of Cardiology. This study highlights the potential use of miR-22 as a diagnostic and therapeutic candidate for cardiovascular diseases.
November 2017 Chemotherapy drugs like doxorubicin show severe side-effects to heart and causes heart failure. IMTTS researchers using a global transcriptomic approach have identified a RNA-binding protein Quaking to play a central role in doxorubicin-induced cardiotoxicity. Overexpression of Quaking by AAV gene therapy reduces the doxorubicin-induced cardiotoxicity. Mechanistically, Quaking was found to regulate formation of cardiac circular RNAs, a novel kind of noncoding RNA. The findings are published in the journal Circulation Research. DOI doi.org/10.1161/CIRCRESAHA.117.311335
November 2017, Oft merkt man erst, wie wichtig Etwas ist, wenn es nicht mehr funktioniert. Diese Tatsache haben sich Forscherinnen und Forscher der Medizinischen Hochschule Hannover (MHH) zunutze gemacht: Mit einer neuen Methode gelang es ihnen, rund 4.000 verschiedene Ribonukleinsäuren (RNAs) in Zellen gezielt auszuschalten, um ihre Funktionen zu entschlüsseln. So konnten sie beispielsweise zeigen, dass eine bestimmte RNA für das Wachstum von Bindegewebszellen (Fibroblasten) notwendig ist. „Die von uns entwickelte Methode kann nun in verschiedenen Studien eingesetzt werden und so helfen, die Entstehung zahlreicher Krankheiten zu entschlüsseln und darauf aufbauend neue Therapien zu finden“, sagt Professor Dr. Dr. Thomas Thum, Leiter des MHH-Instituts für Translationale und Molekulare Therapiestrategien (IMTTS). Die renommierte Fachzeitschrift Cell Death & Differentiation veröffentlichte die Ergebnisse der wissenschaftlichen Studie. Die Ribonukleinsäuren (RNAs), um die es bei dieser neuen Methode geht, sind zum größten Teil noch nicht erforscht. Es handelt sich um verschiedene Arten der langen nicht-codierenden RNA (lncRNA) – also nicht um die RNA, aus der Eiweißbausteine entstehen, sondern um die RNA, die in Zellvorgängen verschiedene regulatorische Aufgaben übernehmen. Wenn diese nicht funktionieren, können sie zur Entstehung schwerer Erkrankungen wie beispielsweise Krebs oder Herzerkrankungen beitragen. Von einigen Dutzenden dieser schätzungsweise mehr als 100.000 lncRNA-Arten haben Forscher in den vergangenen Jahren ihre Funktion herausfinden können – meistens durch den Vergleich aller RNA-Moleküle in gesunden Zellen mit denen in kranken Zellen. „Das Problem bei diesen sogenannten Transkriptom-Analysen ist, dass sich im Zellvergleich oft hunderte bis tausende verschiedene ncRNAs voneinander unterscheiden. So ist es sehr schwierig, herauszufinden, welche der lncRNA-Arten nun mit spezifischen Zellfunktionen und damit der Entstehung von Erkrankungen zusammenhängt“, erläutert die Erstautorin der Studie Dr. Julia Beermann. Mit dem von den MHH-Forscherinnen und -Forschern entwickelten Screening-Verfahren können nun rund 4.000 lncRNAs mit Hilfe von insgesamt 27.000 sogenannten shRNAs stillgelegt werden. Um die Machbarkeit zu testen, haben die Wissenschaftler die shRNAs in Fibroblasten eingeschleust. „Da jede shRNA individuell mit einem Barcode markiert war, konnten wir erkennen, dass der Verlust einer der 4.000 lncRNAs das Wachstum von Fibroblasten stark hemmt. Wir nannten sie Ntep“, erläutert IMTTS-Gruppenleiter Dr. Christian Bär. Als sie „Ntep“ therapeutisch hemmten, konnte sie das Wachstum der Fibroblasten nicht mehr fördern, andere Zelltypen wuchsen normal weiter. „Die krankhafte Vermehrung von Bindegewebszellen in Organen können zum Verlust der Organfunktion führen, beispielsweise in Leber, Lunge, Niere oder Herz. Solche Fibrosen stellen noch immer ein weitgehend ungelöstes Problem dar. Methoden wie diese, die lncRNA als mögliche therapeutische Zielstruktur identifizieren, welche zum Beispiel das Wachstum der Fibroblasten verhindern, sind somit sehr wichtig. Darüber hinaus kann unser neues Verfahren in vielen Studien mit unterschiedlichen Fragestellungen eingesetzt werden“, sagt Professor Thum. Das von ihm geleitete MHH-Institut ist Teil des Integrierten Forschungs- und Behandlungszentrum Transplantation (IFB-Tx) und in den Exzellenzcluster REBIRTH eingebunden.
September 2017, Im Alter treten eine Vielzahl von Krankheiten auf; insbesondere im Herzkreislaufsystem. Im Projekt EXPERT entwickelt das Team von Professor Dr. Dr. med. Thomas Thum vom MHH-Institut für Molekulare und Translationale Therapiestrategien gemeinsam mit Forschern aus fünf weiteren EU-Ländern Therapien für Herzkreislauferkrankungen, die an das Alter des Patienten angepasst sind. Professor Thum koordiniert das Vorhaben. Die EU fördert das Projekt mit insgesamt mehr als 1,4 Millionen Euro für drei Jahre, von denen das MHH-Institut rund 300.000 Euro erhält. Dr. Christian Bär kümmert sich um den Teil der Studie, der in der MHH durchgeführt wird.
June 2017, IMTTS researchers attended the Basic Science Summer school, organized by the European Society of Cardiology, at Sophia-Antipolis – France. The attendance of IMTTS researchers Lisa Peuker and Shambhabi Chatterjee was supported by Career development grants from the Rebirth Cluster of Excellence and Laura Santer was sponsored by “Die Gesellschaft der Freunde der MHH e. V.”. Laura Santer was awarded the best poster prize for her poster presentation entitled ‘Circular RNAs for the therapy of cardiovascular disease’ which showcases the emergence of novel circular RNAs in the cardiovascular field.
May 2017, Within the annual retreat of the Hannover Biomedical Research School (HBRS), Program "Regenerative Sciences", IMTTS researcher Shambhabi Chatterjee has won the award for the best oral presentation of 2nd year PhD students. This achievement highlights the importance of her research focused at the investigation of Telomerase mediated cardioprotection.
May 2017, Haigerloch, (Germany) – 6. KardioWIND Meeting. Ariana Foinquinos won the 2nd prize in the Young Investigator Award session for her presentation on the Pharmacological microRNA modulation for the treatment of heart failure.
Hannover, Germany, May 11th 2017 – Cardior Pharmaceuticals, today announced the completion of a €15 million Series A financing round led by LSP (Life Sciences Partners), Boehringer Ingelheim Venture Fund (BIVF), Bristol-Myers Squibb (BMS), BioMedPartners (with its new BioMedInvest III Fund) and High-Tech Gründerfonds (HTGF). Cardior is pioneering its proprietary RNA technology to revolutionize predicting and treating heart failure. The molecular targets are non-coding RNAs linked to heart failure development that simultaneously control cardiac growth and calcium handling / contractility of cardiomyocytes. The targeting of certain specific non-coding RNAs reverses maladaptive cardiac remodeling and restores normal cardiac function.
“We are very excited to be leading this financing” said Dr. Joachim Rothe, Managing Partner at LSP and a director of Cardior. “There has been a painful lack of scientific and clinical progress in the cardiovascular field for the past 15 years, and Cardior is well positioned to change this.”
In conjunction with this financing, Cardior appointed Dr. Claudia Ulbrich as Chief Executive Officer. Claudia brings with her two decades of operational management and corporate development experience in pharma and biotech including publicly traded companies.
“It is a rare opportunity to develop cutting-edge science in the area of cardiovascular diseases with a high unmet medical need. I am delighted to join Cardior at this exciting development stage of the company and together with its motivated team, quickly put on the map a novel class of drugs and companion diagnostics with the potential to prevent and overcome heart failure” said Dr. Claudia Ulbrich.
“The significant funding raised at this stage of development of the company will provide the resources for an ambitious development plan for our lead compound,” added Prof Thomas Thum, who is joining the management team as Chief Scientific Officer.
With a translational approach and multiple established academic collaborations, Cardior is uniquely positioned to apply innovative first-in-class therapy for myocardial infarction and heart failure patients. Cardior is currently developing non-coding RNA based assets and companion diagnostics. Additionally, Cardior has access to a great variety of discovery programs of undisclosed targets of Prof. Thum’s pipeline.
About Cardior Pharmaceuticals:
Cardior Pharmaceuticals is a privately held German biotech company pioneering the next generation of non-coding RNA based therapeutics in heart failure. Prof Thomas Thum and his team have built a globally renowned expertise in the non-coding RNA field and demonstrated previously their ability to develop & partner innovative drug candidates. The
Medical School Hannover (MHH) and the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) offer a favorable bench-to-bedside environment to support Cardior as one of the world´s leading centers in RNA biology. The intellectual property was licensed from Medical School Hannover (MHH), the Max-Planck- Society (MPG) and from several world renowned French Institutes.
Cardior is the winner of the Startup Challenge at Deutsche Biotechnologietage 2017, the largest German biotech summit. Founded in 2016 by Prof Thum, Cardior was initially supported by VentureVilla Inkubator, hannoverimpuls and Ascenion. For more information, please visit www.cardior.de
Dr. Claudia Ulbrich, CEO, Cardior Pharmaceuticals
+49 511 37484051
Prof. Dr. Dr. Thomas Thum, CSO, Cardior Pharmaceuticals
+49 511 532 5272
LSP (Life Sciences Partners) is a leading independent European investment firm, providing financing for private and public life-science companies. Since the late 1980s, LSP’s management has invested in a large number of highly innovative enterprises, many of which have grown to become leaders in the global life-science industry. With over €1 billion of investment capital raised to date and offices in Amsterdam, Munich and Boston, LSP is one of Europe’s largest and most experienced specialist life-science investors. For more information, please visit www.lspvc.com.
Dr. Joachim Rothe, Managing Partner LSP
+49 (0) 89 330 666-0
Dr. Karin Kleinhans, Associate LSP
+49 (0) 89 330 666-0
April 2017, Mannheim (Germany) – The IMTTS researcher Maria-Teresa Piccoli won the 1st prize of the Young Investigator Award session “Heart Failure” at the 83rd annual meeting of the German Cardiac Society, for her talk titled “Inhibition of the cardiac fibroblast-enriched lncRNA Meg3 hinders MMP-2 induction following pressure overload ameliorating fibrosis and diastolic function”.
March 2017, Münster – The IMTTS researcher Dr. Janika Viereck received the 1st poster prize during the 15th Dutch-German Joint Meeting of the Molecular Cardiology Groups. She has been awarded for her work on the development of a novel therapeutic strategy for the treatment of cardiac hypertrophy and heart failure based on AAV9-mediated delivery on lncRNA H19.
March 2017 IMTTS researcher Ankita Garg has won the award for the best oral presentation of 1st year Ph.D. students in the annual retreat of the Hannover Biomedical Research School (HBRS), Program "Molecular Medicine". This achievement highlights the importance of her research focused on the characterization of mineralocorticoid receptor-induced cardiac remodeling.
November 2016, IMTTS researcher Celina Schauerte received a travel grant by DAAD (Deutscher Akademischer Austauschdienst) to join the “ASN Kidney Week 2016” in Chicago, IL, USA. Her poster was selected as one of the highlights of the poster session by ASN Kidney STARS program.
Celina Schauerte has already been supported last year by DAAD with another travel grant to attend “ASN Kidney Week 2015” in San Diego, CA, USA. In San Diego, her oral presentation was honored as a “top oral abstract by young trainees”.
October 2016, IMTTS researcher Celina Schauerte enrolled in the 2-years interdisciplinary program “Translational Research & Medicine: From Idea to Product” organized via TRAIN (translational alliance in Lower Saxony) academy. She has been accepted for a stipend by REBIRTH cluster of excellence, which covers the costs of participation.
October 2016, Berlin, Germany - IMTTS Researchers Ariana Foinquinos and Dr. Shashi Kumar Gupta received Abstractpreis der Segnitz-Ackermann-Stiftung in Berlin for their abstracts at Basic Science Meeting, DGK Herbstagung.
October 2016 The Hannover Biomedical Research School (HBRS) prize for the best PhD thesis has been awarded to the IMTTS researcher Janika Viereck. She was honored for her excellent doctoral thesis entitled “Non-coding RNAs as ‘theranostics’ in heart, lung and circulation”. Janika Viereck carried out her PhD thesis within the international PhD program “Regenerative Sciences” at the HBRS under the guidance of Prof. Thum. During her PhD she identified a novel long non-coding RNA that is involved in the development of cardiac hypertrophy. Overexpression of this transcript induced pathological heart growth, while antisense-oligonucleotide mediated blockage of the lncRNAs activity prevented and attenuated hypertrophic cardiac remodeling, opening new avenues for therapeutical applications and strategies. In other parts of her work, she investigated the value of circulating miRNAs as performance biomarkers of marathon runners and the consequence of a single nucleotide polymorphism in the surfactant protein D (SP-D) gene on microRNA expression patterns in the lung.
September 2016 Autophagy is a self-renewal process and in a non-dividing cell like cardiomyocytes, it is very important to maintain the cellular homeostasis. Autophagy is regulated by several Atg (Autophagy related genes) genes, but due to their ubiquitous expression, cannot be targeted for therapy. Non-coding RNAs like microRNAs show cell specific/enrich expression pattern and thus cardiomyocyte specific/enrich microRNAs regulating autophagy (cardioautophagomiR) could be easily targeted to modulate cardiomyocyte autophagy. IMTTS reseachers and collaborators identified cardioautophagomiR miR-22 as a strong autophagic inhibitor from precursor miRNA library screening. MiR-22 was found to be increased during natural cardiac aging as well as in pre mature aging model LMNA +/-. Inhibition of miR-22 post myocardial infarction in aging mice improves cardiac function and inhibits cardiac remodeling. Thus, miR-22 could be of therapeutic interest to treat elderly individuals with myocardial infarction in near future. Circulating levels of miR-22 also predicted mortality in heart failure patients depicting its prognostic potential.
The findings were published in the Journal of The American College of Cardiology, October 2016 Issue http://content.onlinejacc.org/article.aspx?articleid=2555931&resultClick=3 .
September 2016 The group of 25 DAAD Postdoc-NeT Fellows visited the REBIRTH Cluster of the medical school. Through its Postdoctoral Researchers’ Networking Tour the DAAD offers a hands-on personalized experience to provide postdoctoral researchers with an insight into German science and the job market for highly qualified postdoctoral researchers. This year’s networking tour focused on molecular bioscience (biochemistry, biotechnology, medicine and related disciplines) and made a stop in Hannover. Several of the researchers (from The Rockefeller University, Albert Einstein College of Medicine, USA and from the University of Macau, China) have visited IMTTS to get insight of our research program, got advice on career opportunities and networking.
March 2016 Mannheim (Germany)-The working group “Chronic heart failure” (AG10) of the German Cardiac Society (DGK) awarded the IMTTS researcher Dr. Jan Fiedler with the 1st prize honoring the endothelial IncRNA publication “Development of long non-coding RNA-based strategies to modulate tissue vascularization” published in the Journal of the American College of Cardiology (JACC) in 2015. The prize award was handed over at the 82nd annual meeting of the DGK.
March 2016, IMTTS researchers attended the 82nd annual meeting of the DGK (German Society of Cardiology) in Mannheim and presented their work on non-coding RNAs for therapy and diagnosis of cardiovascular disease. Additionally, the attendance of IMTTS researchers Katharina Bock, Angela Dettling, Dominique Kirste, Franziska Schöttmer, Felix Kleemiß, Anselm Derda and Jan Kleeberger was supported by travel grants from the DGK.
March 2016, Leiden (Netherlands) - 14th Dutch-German Joint Meeting of the Molecular Cardiology Groups. Ariana Foinquinos won the 2nd prize in the Young Investigator Award session for her presentation on the development of a novel treatment for heart failure after myocardial infarction based on AntimiR-132 delivery.
March 2016 Within the annual retreat of the Hannover Biomedical Research School (HBRS), Program “Molecular Medicine”, IMTTS researcher Celina Schauerte has won the award for the best oral presentation of 3rd year PhD students. Last year, Celina Schauerte already received the award for the best poster presentation of 2nd year PhD students. This success underlines the importance of her research focus regarding the investigation of inhibiting a pro-fibrotic miRNA as a new therapeutic strategy against chronic kidney disease.
February 2016 The human genome is like a giant library harboring billions of books, the collective information of life. Unfortunately, only a handful of ‘documents’ could be uncovered so far. A new read-out of the genome unraveled unexplored genetic information that codes for transcripts that escape protein synthesis and carry out various functions in their unique form as RNAs. Such long non-coding RNAs (lncRNAs) provide novel promising treatment options for heart disease. Among thousands of lncRNAs, IMTTS researcher and coworkers identified one that provokes pathological enlargement of the heart muscle. This lncRNA named Chast, short for cardiac hypertrophy associated transcript, was specifically up-regulated in heart muscle cells of mice with heart failure and its human equivalent showed a comparable increase in diseased hearts of aortic stenosis patients. Chast seems to drive pathological changes in the heart by blocking autophagy, an important recycling process for the recovery of nutrients and cellular components. Inhibition of Chast in mice by molecules counteracting its activity prevented and attenuated the abnormal growth of the heart and improved the pump function. The researchers have published their findings in the journal Science Translational Medicine (February 17th, 2016). The report entitled “Long noncoding RNA Chast promotes cardiac remodeling” can be found here:
In a next step the IMTTS researchers want to develop Chast inhibitors for humans so that patients with diseased or failing hearts can be treated more successfully in future.
January 2016 Les Diableretes (Switzerland) – The Heart Failure Association of the European Socienty of Cardiology (ESC) awarded the IMTTS researcher Janika Viereck with the 1st prize in the Young Investigator Poster Competition. Janika Viereck was honored for her presentation “Inhibition of long noncoding RNA Chast prevents pressure-overload induced cardiac hypertrophy
November 2015 The project “MR-FOCUS – Influence of mineralocorticoid receptor for regulation, diagnostic and therapy of cardiac remodeling” is funded for 3 years with 1.2 million Euro
by both French Agence francaise de financement de la recherche (ANR) and Deutsche Forschungsgemeinschaft (DFG). German applicants are Prof. Dr. Dr. med. Thomas Thum, Institute of Molecular and Translational Therapeutic Strategies (IMTTS) and Prof. Dr. med. Johan Bauersachs, Department of Cardiology and Angiology from Hannover Medical School. Both researchers have a budget of about 700.000 Euro for experimental and translational research on the regulation, diagnostic and therapy targeting the mineralocorticoid receptor (MR) which has a pivotal function during pathological remodeling after myocardial infarction (MI). The overall aim is the development of an improved diagnostic and therapeutic treatment strategy for patients after MI.
October 2015 IMTTS researcher Dr. Jan Fiedler has been accepted for participation in the novel interdisciplinary program “Translational Research & Medicine: From Idea to Product” organized via TRAIN (translational alliance in Lower Saxony) academy. The 2 years program will include different modules aiming to understand the finding, development and application of drug candidates. In addition, IMTTS researcher Dr. Sandor Batkai will also contribute to TRAIN academy program by giving a talk on “Preclinical development of RNA-targeting therapeutics”
July 2015 The Physiological Society invited Dr. Jan Fiedler to give a talk about “Non-coding RNAs in vascular cells and implications for cardiac disease” at the conference “Physiology 2015” in Cardiff, Wales (GB). Franziska Schöttmer and Celina Schauerte both received a travel grant from “Die Gesellschaft der Freunde der MHH e. V.” to attend this meeting and to present their data on the role of non-coding RNAs in cardiovascular and renal diseases.
July 2015 Bordeaux - Prof. Dr. Dr. med. Thomas Thum was awarded with the „Outstanding Investigator Award“ of the International Society of Heart Research (ISHR; see http://www.ishr-europe.org/). The ISHR honors Prof. Thum for his outstanding contributions to cardiovascular research. In groundbreaking studies Prof. Thum and his team discovered new roles of noncoding RNA molecules as new targets and diagnostic markers for cardiovascular disease.
June 2015 Prof. Thum joined the Editorial Board of the European Heart Journal as International Associate Editor.
May 2015 Prof. Thum accepted the invitation to serve as member of the Scientific Advisory Board of the Institut Pasteur de Lille, France.
May 2015 The ESC Working Groups on Myocardial Function and Cellular Biology of the Heart awarded IMTTS member Maria-Teresa Piccoli a poster prize for her presentation “Identification of functional long noncoding RNAs in cardiac fibrosis” during the joint meeting held in Varenna (Italy) from April 30th to May 3rd.
The Oligonucleotide and Peptide Therapeutics Conference (TIDES) took place this year May 3-6 in San Diego, California. The Poster Award of the conference recognizes presenters whose research efforts demonstrate exceptional advances and breakthroughs in the areas of discovery, pre-clinical and clinical aspects of oligonucleotide based therapeutic research. The 2015 Poster Award recipients is Sandor Batkai from IMTTS for his presentation of the study “Therapeutic oligonucleotide-based inhibition of miR-132 as novel treatment of chronic heart failure”. The prize was accompanied by an award of $12,500 in in-kind support from the sponsor, AUM LifeTech, Inc.
May 2015 We identified miR-21 in the heart to be regulated by osteopontin (OPN), an important pro-fibrotic cytokine. OPN and miR-21 were significantly increased in cardiac biopsies of patients with myocardial fibrosis. Ang II infusion via osmotic minipumps led to specific miRNA regulations with miR-21 being strongly induced in wildtype (WT) but not OPN knockout (KO) mice. This was associated with enhanced cardiac collagen content, myofibroblast activation, ERK-MAP kinase as well as AKT signalling pathway activation and a reduced expression of Phosphatase and Tensin Homologue (PTEN) as well as SMAD7 in WT but not OPN KO mice. In contrast, cardiotropic AAV9-mediated overexpression of OPN (adenoviral constructs) in vivo further enhanced cardiac fibrosis. In vitro, Ang II induced expression of miR-21 in WT cardiac fibroblasts, while miR-21 levels were unchanged in OPN KO fibroblasts. As primary miR-21 (pri-miR-21) was also increased by Ang II, we studied potential involved upstream regulators; Electrophoretic Mobility Shift and Chromatin Immunoprecipitation analyses confirmed activation of the miR-21 upstream-transcription factor AP-1 by Ang II. Recombinant OPN directly activated miR-21, enhanced fibrosis and activated the phosphoinositide 3-kinase pathway. Locked nucleic acid-mediated miR-21 silencing ameliorated cardiac fibrosis development in vivo. Our studies thus underline the efficiency of modulating miR-21 in cardiac remodelling and failure. The study has been published 2015 in the European Heart Journal and a link can be found here http://eurheartj.oxfordjournals.org/content/early/2015/04/20/eurheartj.ehv109
May 2015 Professor Dr. Dr. Thomas Thum, Head of IMTTS, received the prestigious „ERC Consolidator Grant“ (European Research Council). He and his team will use the new funding of 1.8 Million Euro for the project LONGHEART, which will study in detail the diagnostic and therapeutic role of long noncoding RNAs in cardiovascular disease, especially cardiac remodelling and heart failure.
April 2015 IMTTS researchers attended the annual meeting of the DGK (German Society of Cardiology) in Mannheim to present their data on the role of non-coding RNAs in cardiovascular diseases. Moreover, the IMTTS researchers Franziska Schöttmer, Filippo Martino, Ariana Foinquinos, Malte Kölling and Celina Schauerte received a travel grant from the DGK to attend this conference.
March 2015 Keystone Symposia on Molecular and Cellular Biology arwarded IMTTS researcher Dr. Jan Fiedler with a scholarship to attend the Keystone Symposium on "Cell Biology of the Heart: Beyond the Myocyte-Centric View".
November 2014 Professor Thomas Thum and Dr. Claudia Bang were awarded the Sir Hans Krebs Prize, which is endowed by the Society of Friends of Hannover Medical School (GdF). They were honored for their research project “Cardiac fibroblast-derived miRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy” published in Journal of Clinical Investigations in April 2014. In their work the IMTTS researchers discovered a novel miRNA-mediated communication mechanism within the myocardium. In particular, miR-21*, a passenger strand microRNA that is normally degraded during miRNA biogenesis, is specifically packed and transported by exosomes from cardiac fibroblasts to cardiomyocytes, in which it induced cellular hypertrophy. The study demonstrated that antagonism of miR-21* by cholesterol-conjugated antagomirs in mice with Ang II-induced cardiac hypertrophy rescued the hypertrophic phenotype. These novel discoveries may give rise to new therapeutic strategies that protect people against heart failure.
November 2014 IMTTS researcher Dr. Seema Dangwal has been awarded with ‘the EFSD- Albert Renold Travel Fellowship’ (€ 8000) for training and initiating collaboration with researchers at Harvard Medical School in 2015. Dr. Seema Dangwal will receive training on laser capture microscopy at Harvard core facility and initiate a collaboration with Prof. Dr. Aristidis Veves, director of Microcirculation lab at Joslin Diabetes centre/ Beth Israel Deaconess Hospital, Boston to investigate the therapeutic potential of miRNAs in accelerating wound healing in diabetic subjects.
October 2014 The IMTTS researchers Dorothee Hartmann, Dr. Shashi Kumar Gupta, Dr. Kristina Sonnenschein and Dr. Claudia Bang received a travel grant from the German Society of Cardiology (DGK) to attend the Basic Science Meeting and autumn meeting of the DGK in Düsseldorf. Moreover, the German Society of Cardiology awarded IMTTS researchers Dorothee Hartmann and Dr. Claudia Bang with the 3rd prize of the Hans-Jürgen-Bretschneider poster award of the Basic Science Meeting in Düsseldorf. Dorothee Hartmann was honoured for her presentation “Identification and functional characterization of GATA2-regulated microRNAs” and Dr. Claudia Bang for her presentation “Hypoxic cardiomyocyte-derived vesicles trigger fibrotic response in cardiac fibroblasts“.
October 2014 Dr. Claudia Bang was awarded the PhD award of the Hannover Biomedical Research School (HBRS) for her excellent thesis with the title “MicroRNAs as regulators and paracrine signalling mediators in cardiac remodelling“. Dr. Claudia Bang carried out her PhD thesis within the PhD program “Molecular Medicine” of the Hannover Biomedical Research School under the guidance of Prof. Dr. Dr. Thum. During her PhD thesis she investigated a novel paracrine miRNA/vesicle‐mediated cross‐talk between cardiac fibroblasts and cardiomyocytes, leading to cardiomyocyte hypertrophy. Moreover, she also studied the role of TWIST1‐driven miR‐199/214 cluster in end‐stage dilated cardiomyopathy.
September 2014 IMTTS researcher Dr. Seema Dangwal has received DFG Funding (DA-1667/1-1, €330,200.00, duration 2014-2017) to study the role of miRNAs in diabetic chronic wound-healing for her independent post-doctoral research. Impaired wound healing is a major cause of lower extremity amputations in diabetic subjects. Dr. Dangwal will investigate genome wide miRNA profile changes in laser capture isolated dermal cells from skin biopsies of DFU subjects with complete healing vs non healing wounds to study in depth in-vitro and in-vivo molecular mechanisms of miRNA mediated gene regulation crucial for tissue repair process. She will further implement oligonucleotide based novel therapeutic approaches to accelerate healing in murine/ rabbit models of diabetic wound healing.
September 2014 The IMTTS group member and medical student Anselm Derda received the Otto-Hess-Promotionsstipendium from the German Cardiac Society (DGK). This one year scholarship supports Anselm Derda in his project “Characterization of cardiac stress (Takotsubo Cardiomyopathy)-related miRNAs ex vivo” and in his dissertation on different forms of cardiomyopathies. He will perform his project in the laboratory of the National Heart and Lung Institute (NHLI) at Imperial College in London under supervision of Prof. Sian Harding (NHLI) and Prof. Thomas Thum.
August 2014 IMTTS researcher Dr. Jan Fiedler received a travel award from the ESC Council on Basic Cardiovascular Science to attend the ESC Congress 2014 in Barcelona. Dr. Fiedler presented recent data on angiogenic non-coding RNAs and was in fruitful discussions with other ESC Congress attendees.
June 2014 IMTTS researcher Dr. Shashi Kumar Gupta received a one year stipendium for the project “MicroRNA-22 mediated regulation of cardiac autophagy” from the German Cardiac Society (DGK). Autophagy is a catabolic process where the cell renews its damaged organelles and non-functional proteins. Altered cardiac autophagy has been reported in various cardiac diseases. Therefore, Dr. Gupta and colleagues screened for microRNAs regulating cardiac autophagy and will use the stipendium to study selected microRNA candidates.
June 2014 IMTTS researcher Dr. Johan Lorenzen and colleagues identified a new mechanism of acute kidney injury based on dysregulation of miR-24. In ischemia-reperfusion (I/R) injury of the kidney, a major cause of AKI, apoptosis-associated miR-24 was found to be upregulated in whole kidneys of mice and in patients after kidney transplantation. Cell-sorting experiments revealed a specific miR-24 enrichment in renal endothelial and tubular epithelial cells after I/R induction. Transient overexpression of miR-24 alone induced apoptosis and altered functional parameters in these cells, whereas silencing of miR-24 ameliorated apoptotic responses and rescued functional parameters in hypoxic conditions. MiR-24 effects were mediated through regulation of H2A histone family, member X, and heme oxygenase 1, which were experimentally validated as direct miR-24 targets. In vivo, silencing of miR-24 in mice before I/R injury resulted in a significant improvement in survival and kidney function, a reduction of apoptosis, improved histologic tubular epithelial injury, and less infiltration of inflammatory cells (see Figure). Overall, these results indicate miR-24 promotes renal ischemic injury by stimulating apoptosis in endothelial and tubular epithelial cell. Therefore, miR-24 inhibition may be a promising future therapeutic option in the treatment of patients with ischemic AKI. The findings have been published in the Journal of the American Society of Nephrology and can be found here.
April 2014 IMTTS researcher Dr. Claudia Bang and colleagues identified a novel paracrine miRNA/exosome-mediated crosstalk between cardiac fibroblasts and cardiomyocytes, leading to cardiomyocyte hypertrophy.
Recently, circulating extracellular miRNAs have emerged as regulators of cell-cell-communication and indicate a role in the mediation of paracrine signaling. Here, miRNA-21* was found to be enriched in fibroblast-derived exosomes compared to the intracellular compartment of these cells. Proteome profiling identified SORBS2 and PDLIM5 as miRNA-21* targets. Silencing of these targets in cardiomyocytes induced hypertrophy. Antagonism of miRNA-21* in mice with Ang II-induced cardiac hypertrophy attenuated pathology.
These findings reveal fibroblast-derived miRNA-21* acting as crucial paracrine signaling mediator during fibroblast-derived cardiomyocyte hypertrophy and shows the potential as a therapeutic target.
(“Cardiac fibroblast-derived microRNA passenger strand-enriched exosomes mediate cardiomyocyte hypertrophy”, J Clin Invest. View this article on PubMed)
March 2014 IMTTS Researchers together with French colleagues identified a novel Biomarker of cardiac remodeling and for prediction of cardiovascular mortality in heart failure patients.
Long non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides in length and lack protein-coding capability. LncRNAs showed potential as candidate biomarkers for the detection of various cancers. In cardiovascular disease the diagnostic utility of circulating lncRNAs has not been investigated so far. This recently published study showed the potential use of circulating lncRNAs in plasma as prognostic biomarkers for heart failure.
Initial lncRNA screening was performed in plasma RNA from patients with myocardial infarction according to the level of left ventricular (LV) remodeling. The mitochondrial lncRNA uc022bqs.1 (LIPCAR) was found to be down-regulated early after myocardial infarction but up-regulated during later stages. LIPCAR levels identified patients developing cardiac remodeling and indicate a strong association with cardiovascular mortality.
(“The Circulating Long Non-Coding RNA LIPCAR Predicts Survival in Heart Failure Patients”, Circ Res. View this article on PubMed)
October 2013 The IMTTS Group Member Shashi Kumar Gupta recently received the HBRS (Hannover Biomedical Research School) PhD Prize for his excellent PhD Thesis. Shashi Kumar Gupta carried out his PhD thesis within the International PhD Program “Molecular Medicine” at HBRS under the guidance of Prof. Thum at the IMTTS. During his PhD work which is titled as “MicroRNAs as therapeutic target in cardiovascular disease”, he found a new microRNA cluster miR-212/132 which regulates both cardiomyocyte hypertrophy and autophagy. Cardiac specific overexpression of miR-212/132 cluster in mice led to death at an early age due to exaggerated hypertrophy and impaired autophagy. Pharmacological inhibition mediated by antisense oligonucleotides of these microRNAs, leds to partial blockage in development of cardiac hypertrophy, paving a way for future therapeutical application. In the other part of his work, he also focussed on evaluation of circulating microRNAs as diagnostic and prognostic biomarker for patients with acute myocardial infarction.
October 2013 The Deutsche Gesellschaft für Kardiologie (DGK) awarded the IMTTS member Claudia Bang with the 1. prize of the Hans-Jürgen-Bretschneider poster award of the Basic Science Meeting in Dresden for her presentation “Cardiac fibroblast-derived microRNAs mediating cardiomyocyte hypertrophy”.
August 2013 IMTTS researchers have identified a novel miRNA family involved in the regulation of angiogenic responses. As transforming growth factor (TGF)-beta is linked to abnormal vessel function and can mediate impairment of endothelial angiogenic responses we studied its effects on microRNAs expression and identified miR-30a-3p, along with other members of the miR-30 family, to be strongly silenced. We identified the epigenetic factor Methyl CpG binding protein 2 (MeCP2) to be a direct and functional target of miR-30a-3p that led to a hypermethylation of the sirtuin1 gene. In vivo, experiments employing endothelial cell-specific MeCP2 null or Sirtuin1 transgenic mice confirmed involvement of MeCP2/Sirt1 in the regulation of angiogenic functions of endothelial cells. The term “epigenetics” is used to describe changes in gene expression mediated by mechanisms other than underlying DNA changes. Our observation that a microRNA in endothelial cells affects downstream epigenetic pathways leading to impaired angiogenic activity opens new avenues for using miRNAs as epigenetic modifiers to develop of novel vascular therapeutic strategies.
The paper has been published in Circulation Research and can be found here: http://www.ncbi.nlm.nih.gov/pubmed/23960241
July 2013 The Imperial College in London is amongst the Top Universities world-wide. Prof. Thomas Thum joined the National Heart and Lung Institute of Imperial College from July 2013 as a visiting professor. This will considerably strengthen cooperative research between the Medical School Hannover and the Imperial College in London in terms of heart failure and transplantation research.
June 2013 Prof. Dr. Dr. Thomas Thum, director of the Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School (MHH), receives together with partners from Europe and the United States 6 Million US dollars from the Leducq Foundation for the “Transatlantic network microRNA-based therapeutic strategies for vessel diseases” (MIRVAD). The scientific aim is to develop new diagnosis possibilities and therapies for vascular diseases, which are based on microRNAs. Prof. Thum is responsible for the finances of the whole network and coordinates the activities European partners. Prof. Bill Sessa from Yale University will organize the US part. Participating are the Hannover Medical School and three partners from Frankfurt, Bristol and London as well as three North American teams from Yale and Worcester. This international research group will focus on the creation, calcification and morbid expansion of blood vessels. The ambitions plan is to prepare microRNA-based diagnostics and therapies for clinical medicine.
The Leducq Foundation is a French foundation, which has the aim to support international research cooperations between Europe and the United States to create alliances without borders in the sector of cardiovascular diseases. For further information please see the following web pages:
More information: Prof. Dr. Dr. Thomas Thum, Director of the Institute of Molecular and Translational Therapeutic Strategies (IMTTS), tel. +49 511 532-5272, Thum.Thomasmh-hannover.de
April 2013 The Deutsche Gesellschaft für Kardiologie (German Society of Cardiology) and Oskar-Lapp Stiftung awarded the Oskar-Lapp Forschungspreis 2013 to Shashi Kumar Gupta from the Institute of Molecular and Translational Therapeutic Strategies (IMTTS) for his work on “The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy’’ published in Nature Communications in Sep 2012. Together with researchers from MPI Göttingen, the researchers show that the miR-212/132 cluster is induced during pressure overload and causes cardiomyocyte hypertrophy and impaired autophagy in cardiomyocytes. Overexpression of the miR-212/132 cluster was detrimental while inhibition resulted in protection from pressure-overload induced cardiac hypertrophy. This study paves a way for future miRNA based therapeutics for treatment of heart failure patients.
March 2013 The first PV User Group Meeting with the participation around 30 scientists across Europe and the US took place at the Hannover Medical School on March 15, 2013. The meeting was organized by Dr. Sandor Batkai and co-hosted by Prof. Thum at the Institute for Molecular and Translational Therapeutic Strategies. PV measurements are the gold standard for cardiac function assessment, used by scientist in various animal models and also by clinicians. The first User Group Meeting provided a unique opportunity to meet experts and discuss topics specific to PV research - including calibration, surgical techniques, phenotyping of small and large animal cardiac disease models, and comparability across laboratories. Guest Speaker was Pal Pacher, MD, PhD, FAHA, FACC, FAPS, from the National Institutes of Health, USA.
March 2013 Long non-coding RNAs (long ncRNAs, lncRNA) are non-protein coding transcripts longer than 200 nucleotides. This somewhat arbitrary limit distinguishes long ncRNAs from small regulatory RNAs such as microRNAs (miRNAs), short interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. Recently, lncRNAs were shown to be additional involved in regulatory processes of cells. Dr. Kumarswamy Regalla and Prof. Thomas Thum from IMTTS received now a 3 year funding to study the role of lncRNAs in cardiac hypertrophy and heart failure.
February 2013 IMTTS researchers Fiedler, Batkai, Gupta and Thum receive a significant 2-year funding for the project “Towards clinical applications of microRNA-based treatment strategies of cardiac remodelling” from the Deutsche Herzstiftung. The funded project investigates the functional relevance of a miR cluster in cardiac ischemia. Based on the findings in murine model of myocardial infarction also larger animal studies are planned to further translate miR therapeutics into the clinics.
February 2013 The HOMAGE (Heart OMics in AGEing) project, coordinated by the French National Institute of Health and Medical Research (INSERM), has been awarded a grant by the European Commission for a 6 year period. The project aims to identify and validate specific biomarkers of heart failure in order to prevent the development of the disease affecting elderly population. 17 research groups from 10 countries will collaborate to investigate new ways of preventing heart failure. The project will use an innovative ‘omic-based’ approach which investigating simultaneously a huge amount of genes, proteins and metabolites. The 17 partners will have met at Nancy on February 22nd for the kick off meeting of HOMAGE.
The HOMAGE consortium will manage cohorts for a total of 30 000 patients. The European researchers will firstly identify biomarker candidates in blood and study their predictive value for heart failure and common co-morbidities associated with ageing (renal impairment, cognitive disorders…). Subsequently, HOMAGE will lead a clinical trial to look for novel treatments of heart failure that can be targeted specifically to those patients at risk. This trial will allow identifying patients’ omics based biomarker profiles most likely to predict response to treatment with the better benefit/risk ratio, an attempt into personalized medicine. Researchers at IMTTS will specifically investigate the diagnostic and prognostic power of circulating microRNAs in elderly heart failure patients within the next 6 years. Details can be found at: http://www.homage-hf.eu/
January 2013 Dr. Seema Dangwal from the IMTTS received a Research Stipendium from the Diabetes Foundation 'DHD' of the German Diabetes Society. She will use the award to continue her research about the role of regulatory RNAs in platelet activation in diabetes.
October 2012 IMTTS researchers developed together with colleagues from the University of Bochum a new diagnostic test for Multiple Sclerosis (MS) based on the determination of microRNAs in the cerebrospinal fluid (CSF) of patients. Worldwide there are about 2.5 million affected individuals with MS. Surprisingly, the researchers found certain enriched miRNAs stably detectable in the CSF. After global miRNA profiling, a set of miRNAs was identified that was differentially regulated in patients with MS when compared with that of affected individuals by other neurological diseases. Importantly, the miRNA patterns differentiated relapsing-remitting from secondary progressive MS courses with enormous specificity and sensitivity. Despite the preliminary character of the promising initial data, the results provide rationale for a confirmation study in larger MS cohorts. This approach may substantially improve the diagnosis and provide prognostic information about patients affected by MS. Details about this study can be found at http://www.ncbi.nlm.nih.gov/pubmed/23077021.
September 2012 New therapies for conditions such as cardiac hypertrophy and heart failure are needed and may be developed as a result of a better understanding of the tight regulation of gene transcription in heart muscle cells. We previously showed blocking certain small RNA molecules, so called microRNAs, in the heart to prevent the development of heart failure. IMTTS researchers from MHH together with researchers from the Max Planck Institute in Göttingen have now established that the micro-RNA molecules miR-212 and miR-132 play an important role in determining the ability of cardiomyocytes to regulate cardiac growth and a process called autophagy. During autophagy, the cells break down and reuse components that are no longer needed. The researchers have published their findings in Nature Communications (25 September 2012). The title of the paper is: “The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy” and can be found online here: http://www.nature.com/ncomms/journal/v3/n9/full/ncomms2090.html
The next step for the IMTTS researchers is now developing this strategy for clinical use in humans, as micro-RNA inhibitors, alone or in combination with conventional treatments, could represent a promising new therapeutic approach.
July 2012 The European Foundation for the Study of Diabetes (EFSD) and Sanofi-Aventis recently started the European Research Programme in Micro- and Macrovascular Complications of Diabetes. Researchers at IMTTS (Dr. Seema Dangwal) now received a considerable grant to study the effects of diabetes on microRNA biogenesis and function in platelets. Diabetes is a pro-coagulatory state characterized by enhanced platelet activation, aggregation and adhesion that shifts the normal hemostatic balance towards thrombosis and increases the risk of coronary artery disease. Platelets play an important role in general hemostasis maintenance and pathophysiology of thrombosis. Preliminary data about the abundance of miRNAs in platelets suggests that a distinct miRNA network may regulate the platelet gene expression. Clinical data regarding platelet miRNA expression patterns and their interaction with platelet mRNA in diabetes is scarce. The proposed study funded by EFSD/Sanofi will now reveal novel miRNAs candidates and will identify yet undiscovered molecular mechanisms in platelet gene modulation influencing platelet dysfunction in diabetic settings.
More details about the Foundation can be found here: http://www.europeandiabetesfoundation.org/
“Prevention of ischemic/reperfusion injury by miRNA inhibition:
Towards new mechanisms and clinical applications“
June 2012 Patients suffering from acute myocardial infarction (MI) need fast and efficient treatment to prevent/attenuate myocardial tissue injury. Immediate interventions successfully rescue cardiac oxygen deprivation (ischemia) by re-opening of the infarcted/occluded vessel (reperfusion) to minimize infarct progression and thus sustain and stabilize cardiac performance. Insufficient myocardial capillary density after MI has been identified as a critical event in the remodelling process that can be targeted with novel therapeutic strategies. Mimicking cardiac ischemia/reperfusion injury (IR) in mice by occluding the mid left anterior descending artery (LAD) followed by reperfusion is a well-characterized and, importantly, clinically relevant model to study the molecular mechanisms of the development of cardiac injury following MI.
Very recently our group showed that a MI-induced endothelial miRNA was capable to regulate angiogenic responses and overall vascularity of the heart in a murine permanent myocardial infarction model. Specifically, with this grant (received by Dr. Jan Fiedler) we now will focus on the efficacy of antagomir application in clinical relevant murine and large-animal cardiac ischemia/reperfusion injury models.
June 2012 Prof. Thum was asked and joined the Editorial Board of the journal Circulation Research. Circulation Research is a biweekly peer-reviewed medical journal published by Lippincott Williams & Wilkins and is the official journal of both the American Heart Association and the Council on Basic Cardiovascular Sciences of the American Heart Association. The journal focuses on fundamental research, translational research, translational science, and clinical research on all topics pertaining to cardiovascular system issues. A link to the journal can be found here: http://circres.ahajournals.org/
Mai 2012 Die Deutsche Gesellschaft für Kardiologie (DGK) verleiht den Franz-Maximilian-Groedel-Forschungspreis an Herrn Prof. Dr. Dr. med. Thomas Thum und Herrn Dr. rer. nat. Jan Fiedler, Institut für Molekulare und Translationale Therapiestrategien (IMTTS, IFB-Tx) für ihre gemeinsame Forschungsarbeit “MicroRNA-24 Regulates Vascularity After Myocardial Infarction“.
April 2012 Physiological aging and senescence are associated to progressive decline in most physiological functions, reduced response to stress, loss of viability and increased susceptibility to various diseases. Cardiac aging is associated with reduced cardiac functional reserve, left ventricular hypertrophy, mild fibrosis and reduced endogenous cardiac protection. IMTTS researchers have identified miRNAs differentially regulated during cardiac postnatal development and aging. MiR-22 was most prominently upregulated during cardiac aging. Cardiac expression of its bioinformatically predicted target mimecan (osteoglycin, OGN) was gradually decreased with advanced age. Luciferase reporter assays validated mimecan as a bona fide miR-22 target. Both, miR-22 and its target mimecan were co- expressed in cardiac fibroblasts and smooth muscle cells. Functionally, miR-22 overexpression induced cellular senescence and promoted migratory activity of cardiac fibroblasts. Small interference RNA-mediated silencing of mimecan in cardiac fibroblasts mimicked the miR-22-mediated effects. In conclusion, miR-22 upregulation in the aging heart contributed at least partly to accelerated cardiac fibroblast senescence and increased migratory activity. These results suggest an involvement of miR-22 in age-associated cardiac changes, such as cardiac fibrosis. Details about the work can be found here:
Jazbutyte V, Fiedler J, Kneitz S, Galuppo P, Just A, Holzmann A, Bauersachs J, Thum T. MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart. Age (Dordr). (2012) Epub ahead of print.
February 2012 Researchers from IMTTS report a new finding about cardiovascular microRNAs. Impaired myocardial sarcoplasmic reticulum calcium-ATPase 2a (SERCA2a) activity (a system critically involved in intracardial calcium homeostasis) is a hallmark of failing hearts. SERCA2a gene therapy improves cardiac function in animals and patients with heart failure and thus maybe a promising new therapeutic entry point for heart failure therapy. Researchers from IMTTS now collaborated with the Imperial College London and the Mount Sinai School of Medicine, New York and identified microRNAs (important regulators of gene expression) by high-throughput screening that are deregulated in heart failure but normalized by SERCA2a gene therapy. In detailed studies the teams showed SERCA2a gene therapy of failing hearts to restore miRNA-1 (miR-1) expression by an AKT/FoxO3A-dependent pathway leading to normalized expression of the sodium/calcium exchanger 1 and improved cardiac function. This is also the first study showing changes of calcium levels to result in regulation of cardiac microRNA expression. The details about this work can be found here:
Kumarswamy R, Lyon AR, Volkmann I, Mills AM, Bretthauer J, Pahuja A, Geers-Knörr C, Kraft T, Hajjar RJ, Macleod KT, Harding SE, Thum T. SERCA2a gene therapy restores microRNA-1 expression in heart failure via an Akt/FoxO3A-dependent pathway. Eur Heart J. (2012). Epub ahead of print.
November 2011 An IMTTS research team screened for microRNAs involved in endothelial-mesenchymal transition (endMT). This process has previously been shown to contribute to fibroblast formation in fibrotic diseases of the kidney, lung, liver and the heart. TGF-beta is particularly involved in cardiac fibrosis partly by stimulation of endothelial-to-mesenchymal transition. TGF-beta treatment of endothelial cells significantly increased miR-21 expression and induced EndMT characterized by suppression of endothelial and increase of fibroblast markers. Importantly, miR-21 blockade by transfection of specific miRNA inhibitors partly prevented TGF-beta-induced EndMT. Mechanistically, miR-21 silenced phosphatase and tensin homolog (PTEN) in endothelial cells resulting in activation of the Akt-pathway. Akt inhibition partly restored TGF-beta-mediated loss of endothelial markers during EndMT. In vivo, pressure overload of the left ventricle led to increased expression of miR-21 in sorted cardiac endothelial cells, which displayed molecular and phenotypic signs of EndMT (Figure). This was attenuated by treatment of mice subjected to left ventricular pressure overload with an antagomir against miR-21.
Thus, we showed that TGF-beta-mediated EndMT is regulated at least in part by miR-21 via the PTEN/Akt pathway. Of therapeutic importance, anti-fibrotic effects of miR-21 antagonism were partly mediated by blocking EndMT under stress conditions.
Kumarswamy R, Volkmann I, Jazbutyte V, Dangwal S, Park DH, Thum T. Transforming Growth Factor-β-Induced Endothelial-to-Mesenchymal Transition Is Partly Mediated by MicroRNA-21. Arterioscler Thromb Vasc Biol. (2011) Epub ahead of print.
September 2011 IMTTS researchers have successfully implemented a fully-automated robotic-assisted miRNA library screening platform for high-throughput identification of functionally relevant microRNAs. With this method hundreds of different miRNAs can be overexpressed or silenced in basically any target cell with subsequent testing of functional consequences. Researchers of IMTTS together with the REBIRTH-Group Reprogramming of the Hannover Medical School used this platform to screen for functional miRNAs stimulating generation of induced pluripotent stem cells (iPSCs). By this approach a new miRNA family (miR-130/301/721) was identified as an important regulator of iPSC induction by targeting the homeobox transcription factor Meox2 (also known as Gax). Meox2-specific silencing mimicked the effects of this miRNA family on reprogramming. Mechanistically, miRNA-resistant Meox2 overexpression abrogated effects of miR-130/301/721 on reprogramming. In conclusion, researchers have identified a fundamental new mechanism of miRNA/Meox2-dependent regulation of pluripotency. Actual work now focuses on identification of miRNAs important for cardiovascular differentiation of iPSCs.
For further information about cooperations regarding the functional miRNA library platform please contact Prof. Dr. T. Thum.
August 2011 The European Society of Cardiology (ESC) honours Prof. Thomas Thum of the Hannover Medical School with an Outstanding Achievement Award. With this award the ESC Council for Basic Cardiovascular Science annually honours two basic researchers with outstanding accomplishments in the early stage of their career. At the ESC Congress in Paris Prof. Thum, together with fellow awardee Professor Gepstein from the Technion in Israel, received a honorary plaque and 3.000 Euros.
Read more about Prof. Thum’s recent research.
The European Society of Cardiology represents over 62,000 cardiology professionals across Europe and the Mediterranean. Its mission is to reduce the burden of cardiovascular disease in Europe.
August 2011 Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood. Our group now identified that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Further downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2-associated death promoter) and Sirtuin1 were identified by transcriptome, protein arrays, and chromatin immunoprecipitation analyses. Overexpression of miR-24 or silencing of its targets significantly impaired angiogenesis in zebrafish embryos. Blocking of endothelial miR-24 limited myocardial infarct size of mice via prevention of endothelial apoptosis and enhancement of vascularity, which led to preserved cardiac function and survival. We show that miR-24 acts as a critical regulator of endothelial cell apoptosis and angiogenesis and is suitable for therapeutic intervention in the setting of ischemic heart disease.
Fiedler J, Jazbutyte V, Kirchmaier BC, Gupta SK, Lorenzen J, Hartmann D, Galuppo P, Kneitz S, Pena JT, Sohn-Lee C, Loyer X, Soutschek J, Brand T, Tuschl T, Heineke J, Martin U, Schulte-Merker S, Ertl G, Engelhardt S, Bauersachs J, Thum T. MicroRNA-24 regulates vascularity after myocardial infarction. Circulation (2011). Epub ahead of print.
August 2011 MicroRNAs (miRNAs) are small ribonucleotides regulating gene expression. Circulating miRNAs are remarkably stable in the blood. We now tested whether miRNAs are also detectable in urine and may serve as new predictors of outcome in renal transplant patients with acute rejection. We profiled urinary miRNAs of stable transplant patients and transplant patients with acute rejection. The miRs-10a, miR-10b and miR-210 were strongly deregulated in urine of the patients with acute rejection. We confirmed these data in urine of a validation cohort of 62 patients with acute rejection, 19 control transplant patients without rejection and 13 stable transplant patients with urinary tract infection by quantitative RT-PCR. We identified miR-210 to differ between patients with acute rejection when compared to stable transplant patients with urinary tract infection or transplant patients before/after rejection. Low miR-210 levels were associated with higher decline in GFR 1 year after transplantation. Selected miRNAs are strongly altered in urine of the patients with acute renal allograft rejection. Urinary miR-210 level identify patients with acute rejection and predict long-term kidney function. Urinary miR-210 may thus serve as a novel biomarker of acute kidney rejection.
Lorenzen, J.M., Volkmann, I., Fiedler, J., Schmidt, M., Scheffner, I., Haller, H., Gwinner, W., Thum, T. In press. Urinary miR-210 as a mediator of acute T-cell mediated rejection in renal allograft recipients. Am J Transplant. (2011). Epub ahead of print.
July 2011 Circulating microRNAs may have diagnostic potential in acute coronary syndrome (ACS). Previous studies, however, were based on low patient numbers and could not assess the relation of microRNAs to clinical characteristics and their potential prognostic value. We assessed the diagnostic and prognostic value of all major cardiomyocyte-enriched microRNAs in the context of clinical variables and a sensitive myonecrosis biomarker in a large ACS cohort. MiR-1, miR‑133a, miR-133b, miR-208a, miR-208b, and miR-499 concentrations were measured by quantitative reverse transcription PCR in plasma samples obtained on admission from 444 patients with ACS. Patients were followed for 6 months regarding all-cause mortality. Patients with myocardial infarction presented with higher levels of miR-1, miR-133a, and miR‑208b compared with patients with unstable angina. MiR-133a and miR-208b levels were significantly associated with the risk of death in univariate and age- and gender-adjusted analyses. Both microRNAs lost their independent association with outcome upon further adjustment for hsTnT. The present study tempers speculations about the potential usefulness of cardiomyocyte-enriched microRNAs as diagnostic or prognostic markers in ACS.
Widera C, Gupta SK, Lorenzen JM, Bang C, Bauersachs J, Bethmann K, Kempf T, Wollert KC, Thum T. Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome. J Mol Cell Cardiol. (2011). Epub ahead of print
July 2011 Dr. Sandor Batkai was awarded a three year Marie Curie Grant by the European Commission to support his professional reintegration to Germany. Dr. Batkai was head of the Cardiovascular Phenotyping Core at the National Institute on Alcohol Abuse and Alcoholism (NIAAA, Bethesda, USA) from 2004 to 2011. Since June 2011 he is a group leader at the Institute of Molecular and Translational Therapeutic Strategies. His research focuses on the role of microRNAs in pharmacologically induced cardioprotective mechanisms. He aims to develop and test microRNA based therapies in small and large animal models of myocardial infarction and congestive heart failure.