AG Poller

MOLECULAR THERAPY AND RNA TECHNOLOGIES

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MOLECULAR THERAPY AND RNA TECHNOLOGIES

The unifying research theme of our working group is the use of high throughput screening strategies for the identification of new therapeutic targets in heart failure and cardiomyopathies, and the development of novel molecular therapies for their treatment. The search for new therapeutic targets is increasingly focused upon immune-related processes and noncoding RNAs including microRNAs, long noncoding RNAs, and RNA interference. M.D. and Ph.D. students who are interested in these topics are most welcome to contact us wolfgang.poller(at)charite.de or martina.gast(at)charite.de.

Current and recent Ph.D. students and their work:

  • Martina Gast: Cardiovascular RNA interference therapy: the broadening tool and target spectrum. Circ Res 2013.
  • Juliane Tank: Single-target RNA interference for the blockade of multiple interacting proinflammatory and profibrotic pathways in cardiac fibroblasts. J Mol Cell Cardiol 2014.
  • Stefanie Krohn: Matricellular signaling molecule CCN1 attenuates experimental autoimmune myocarditis by acting as a novel immune cell migration modulator. Circulation 2010.
  • Lennart Suckau: Long-term cardiac-targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy. Circulation 2009.

Cooperation partners in cardiovascular immunology:

  • Antje Voigt: Ubiquitin-Like Protein ISG15 in host defense against heart failure in a mouse model of virus-induced cardiomyo-pathy. Circulation 2014.
  • Carmen Scheibenbogen: CCN1: a novel inflammation-regulated biphasic immune cell migration modulator. Cell Mol Life Sci 2012.
  • Ursula Rauch: Protease-activated receptor-2 regulates the innate immune response to viral infection in a coxsackievirus B3-induced myocarditis. JACC 2013.
  • Dirk Westermann (Hamburg): Cardiac fibroblasts support cardiac inflammation in heart failure. Basic Res Cardiol 2014.
  • Carsten Skurk: Adiponectin protects against Toll-like receptor 4-mediated cardiac inflammation and injury. Cardiovasc Res. 2013.

Cooperation partners in molecular therapy and RNA technologies:

  • Roger Hajjar (New York), Stefanie Dimmeler (Frankfurt), Ziya Kaya (Heidelberg), Shinichi Nakagawa (Wako)

NEW THERAPEUTIC TARGETS

Due to the translational nature of our research topic, we conduct most of our current work in close cooperation with clinical research colleagues. Through a research network we have also access to transregional patient cohorts and biosamples collected in years 2004 - 2013 www.sfb-transregio-19.de. During the search for novel therapeutic targets, we recently identified microRNAs {Kuehl, 2015 #8210} and immune-related proteins {Escher, 2014 #8101} which on the one hand are useful as clinical prognostic biomarkers, on the other may constitute new targets for therapeutic modulation.
Our own research and that of cooperation partners has recently focused on "immune system - heart interactions" as an important driving force for disease progression in cardiomyopathies and heart failure. With this in mind we currently study circulating immune-related markers reflecting the status of the diseased heart. This work evaluates novel markers (ncRNAs) associated with circulating exosomes or circulating immune cells (PBMCs) and test if these easily accessible markers have prognostic potential.
We hypothesize that exosomal signaling from irreversibly injured hearts is different from that from hearts with still ongoing pathomechanisms involving innate/adaptive immunity. Whereas traditional protein-type markers are not released before severe or irreversible injury to the cells has occurred, altered packaging and exosome-mediated release of "stress-indicators" may occur much earlier during any pathogenetic process imposing stress (e.g. volume or pressure overload, ischemia, infection) on the heart. Alongside these exosomal studies, PBMC-associated ncRNAs markers will be evaluated regarding their potential to distinguish irreversibly injured hearts from those with still ongoing pathomechanisms, with particular attention to immune-related local or systemic mechanisms. The latter may constitute new therapeutic targets.     

Cooperation partners in molecular therapy and RNA technologies:

  • Differential Cardiac microRNA Expression Predicts the Clinical Course in Human Enterovirus Cardiomyopathy. Kuehl U, Lassner D, Gast M, Stroux A, Rohde M, Siegismund C, Wang X, Escher F, Gross M, Skurk C, Tschoepe C, Loebel M, Scheibenbogen C, Schultheiss HP, Poller W. Circ Heart Fail. 2015 Mar 11. pii: CIRCHEARTFAILURE.114.001475. [Epub ahead of print]
  • Presence of perforin in endomyocardial biopsies of patients with inflammatory cardiomyopathy predicts poor outcome. Escher F, Kühl U, Lassner D, Stroux A, Westermann D, Skurk C, Tschöpe C, Poller W, Schultheiss HP. Eur J Heart Fail. 2014 Oct;16(10):1066-72. doi: 10.1002/ejhf.148. Epub 2014 Aug 28.

NEW THERAPEUTIC TOOLS

Figure 1 – Overview of therapeutic technologies
Figure 2 – Overview of noncoding RNAs

New therapeutic targets of high interest may be related to common HF recovery markers. Recent new molecular targets with broad relevance unconfined to specific etiologies include regulators of myocardial Ca2+ cycle. Related therapies are SERCA2A gene transfer {Greenberg, 2014 #7997} and PLB ablation using RNA interference {Suckau, 2009 #6640}. Another target is miR-25 which was identified by ex vivo screening for modulators of cardiomyocyte function. It was then found that miR-25 inhibition improves cardiac contractility in the failing heart in vivo {Wahlquist, 2014 #7948}. Former publications from our group regarding gene or RNA based therapies of heart failure and cardiomyopathies are given below.
Along these strategies of research, we currently try to identify "myocardial recovery" targets by screening particularly well characterized HF patients under maximum therapy who show differential response to treatment. We have identified potential noncoding RNA targets (miRs, lncRNAs) which are now being further evaluated. The therapeutic tools employed by our group include AAV9 vectors for gene and RNAi therapy targeted to the heart in vivo, and synthetic small RNAs (siRNAs, miR mimics, ASOs) delivered directly or using nanoparticles.

PUBLICATIONS ON MOLECULAR THERAPIES

  • A novel artificial microRNA expressing AAV vector for phospholamban silencing in cardiomyocytes improves Ca2+ uptake into the sarcoplasmic reticulum. Gröβl T, Hammer E, Bien-Möller S, Geisler A, Pinkert S, Röger C, Poller W, Kurreck J, Völker U, Vetter R, Fechner H.PLoS One. 2014 Mar 26;9(3):e92188. doi: 10.1371/journal.pone. 0092188. eCollection 2014.
  • Single-target RNA interference for the blockade of multiple interacting proinflammatory and profibrotic pathways in cardiac fibroblasts. Tank J, Lindner D, Wang X, Stroux A, Gilke L, Gast M, Zietsch C, Skurk C, Scheibenbogen C, Klingel K, Lassner D, Kühl U, Schultheiss HP, Westermann D, Poller W. J Mol Cell Cardiol. 2014 Jan;66:141-56. doi: 10.1016/j.yjmcc.2013.11.004. Epub 2013 Nov 12.
  • Cardiovascular RNA interference therapy: the broadening tool and target spectrum. Poller W, Tank J, Skurk C, Gast M. Circ Res. 2013 Aug 16;113(5):588-602. doi: 10.1161/CIRCRESAHA.113.301056. Review.
  • Endogenous migration modulators as parent compounds for the development of novel cardiovascular and anti-inflammatory drugs. Poller W, Rother M, Skurk C, Scheibenbogen C. Br J Pharmacol. 2012 Apr;165(7):2044-58. doi: 10.1111/j.1476-5381.2011.01762.x. Review.
  • microRNA122-regulated transgene expression increases specificity of cardiac gene transfer upon intravenous delivery of AAV9 vectors. Geisler A, Jungmann A, Kurreck J, Poller W, Katus HA, Vetter R, Fechner H, Müller OJ. Gene Ther. 2011 Feb;18(2):199-209. doi: 10.1038/gt.2010.141. Epub 2010 Nov 4.
  • Development of novel cardiovascular therapeutics from small regulatory RNA molecules--an outline of key requirements. Poller W, Fechner H. Curr Pharm Des. 2010;16(20):2252-68. Review.
  • Cardiac-targeted delivery of regulatory RNA molecules and genes for the treatment of heart failure. Poller W, Hajjar R, Schultheiss HP, Fechner H. Cardiovasc Res. 2010 Jun 1;86(3):353-64. doi: 10.1093/cvr/cvq056. Epub 2010 Feb 22. Review.
  • Long-term cardiac-targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy. Suckau L, Fechner H, Chemaly E, Krohn S, Hadri L, Kockskämper J, Westermann D, Bisping E, Ly H, Wang X, Kawase Y, Chen J, Liang L, Sipo I, Vetter R, Weger S, Kurreck J, Erdmann V, Tschope C, Pieske B, Lebeche D, Schultheiss HP, Hajjar RJ, Poller WC. Circulation. 2009 Mar 10;119(9):1241-52. doi: 10.1161/CIRCULATIONAHA.108.783852. Epub 2009 Feb 23.
  • Cardiac-targeted RNA interference mediated by an AAV9 vector improves cardiac function in coxsackievirus B3 cardiomyopathy. Fechner H, Sipo I, Westermann D, Pinkert S, Wang X, Suckau L, Kurreck J, Zeichhardt H, Müller O, Vetter R, Erdmann V, Tschope C, Poller W. J Mol Med (Berl). 2008 Sep;86(9):987-97. doi: 10.1007/s00109-008-0363-x. Epub 2008 Jun 12.
  • Differential internalization and nuclear uncoating of self-complementary adeno-associated virus pseudotype vectors as determinants of cardiac cell transduction. Sipo I, Fechner H, Pinkert S, Suckau L, Wang X, Weger S, Poller W.
  • Coxsackievirus B3 and adenovirus infections of cardiac cells are efficiently inhibited by vector-mediated RNA interference targeting their common receptor. Fechner H, Pinkert S, Wang X, Sipo I, Suckau L, Kurreck J, Dörner A, Sollerbrant K, Zeichhardt H, Grunert HP, Vetter R, Schultheiss HP, Poller W. Gene Ther. 2007 Jun;14(12):960-71. Epub 2007 Mar 22.
  • Genomic expression profiling of human inflammatory cardiomyopathy (DCMi) suggests novel therapeutic targets. Wittchen F, Suckau L, Witt H, Skurk C, Lassner D, Fechner H, Sipo I, Ungethüm U, Ruiz P, Pauschinger M, Tschope C, Rauch U, Kühl U, Schultheiss HP, Poller W. J Mol Med (Berl). 2007 Mar;85(3):257-71. Epub 2006 Nov 15.
  • Highly efficient and specific modulation of cardiac calcium homeostasis by adenovector-derived short hairpin RNA targeting phospholamban. Fechner H, Suckau L, Kurreck J, Sipo I, Wang X, Pinkert S, Loschen S, Rekittke J, Weger S, Dekkers D, Vetter R, Erdmann VA, Schultheiss HP, Paul M, Lamers J, Poller W. Gene Ther. 2007 Feb; 14(3):211-8. Epub 2006 Oct 5.
  • Induction of coxsackievirus-adenovirus-receptor expression during myocardial tissue formation and remodeling: identification of a cell-to-cell contact-dependent regulatory mechanism. Fechner H, Noutsias M, Tschoepe C, Hinze K, Wang X, Escher F, Pauschinger M, Dekkers D, Vetter R, Paul M, Lamers J, Schultheiss HP, Poller W. Circulation. 2003 Feb 18;107(6):876-82.

PUBLICATIONS ON MYOCARDIAL IMMUNOLOGY

  • Ubiquitin-like protein ISG15 (interferon-stimulated gene of 15 kDa) in host defense against heart failure in a mouse model of virus-induced cardiomyopathy. Rahnefeld A, Klingel K, Schuermann A, Diny NL, Althof N, Lindner A, Bleienheuft P, Savvatis K, Respondek D, Opitz E, Ketscher L, Sauter M, Seifert U, Tschöpe C, Poller W, Knobeloch KP, Voigt A. Circulation. 2014 Oct 28;130(18):1589-600. doi: 10.1161/CIRCULATIONAHA.114. 009847. Epub 2014 Aug 27.
  • Cardiac fibroblasts support cardiac inflammation in heart failure. Lindner D, Zietsch C, Tank J, Sossalla S, Fluschnik N, Hinrichs S, Maier L, Poller W, Blankenberg S, Schultheiss HP, Tschöpe C, Westermann D. Basic Res Cardiol. 2014;109(5):428. doi: 10.1007/s00395-014-0428-7. Epub 2014 Aug 3.
  • Improved diagnosis of idiopathic giant cell myocarditis and cardiac sarcoidosis by myocardial gene expression profiling. Lassner D, Kühl U, Siegismund CS, Rohde M, Elezkurtaj S, Escher F, Tschöpe C, Gross UM, Poller W, Schultheiss HP. Eur Heart J. 2014 Aug 21;35(32):2186-95. doi: 10.1093/eurheartj/ehu101. Epub 2014 Mar 24.
  • Protease-activated receptor-2 regulates the innate immune response to viral infection in a coxsackievirus B3-induced myocarditis. Weithauser A, Bobbert P, Antoniak S, Böhm A, Rauch BH, Klingel K, Savvatis K, Kroemer HK, Tschope C, Stroux A, Zeichhardt H, Poller W, Mackman N, Schultheiss HP, Rauch U. J Am Coll Cardiol. 2013 Nov 5;62(19):1737-45. doi: 10.1016/j.jacc.2013.05.076. Epub 2013 Jul 17.
  • Adiponectin protects against Toll-like receptor 4-mediated cardiac inflammation and injury. Jenke A, Wilk S, Poller W, Eriksson U, Valaperti A, Rauch BH, Stroux A, Liu P, Schultheiss HP, Scheibenbogen C, Skurk C. Cardiovasc Res. 2013 Aug 1;99(3):422-31. doi: 10.1093/cvr/cvt118. Epub 2013 May 13.
  • Adiponectin modulates NK-cell function. Wilk S, Jenke A, Stehr J, Yang CA, Bauer S, Göldner K, Kotsch K, Volk HD, Poller W, Schultheiss HP, Skurk C, Scheibenbogen C. Eur J Immunol. 2013 Apr;43(4):1024-33. doi: 10.1002/eji.201242382. Epub 2013 Mar 1.
  • CCN1: a novel inflammation-regulated biphasic immune cell migration modulator. Löbel M, Bauer S, Meisel C, Eisenreich A, Kudernatsch R, Tank J, Rauch U, Kühl U, Schultheiss HP, Volk HD, Poller W, Scheibenbogen C. Cell Mol Life Sci. 2012 Sep;69(18):3101-13. doi: 10.1007/s00018-012-0981-x. Epub 2012 Apr 20.
  • Reduced degradation of the chemokine MCP-3 by matrix metalloproteinase-2 exacerbates myocardial inflammation in experimental viral cardiomyopathy. Westermann D, Savvatis K, Lindner D, Zietsch C, Becher PM, Hammer E, Heimesaat MM, Bereswill S, Völker U, Escher F, Riad A, Plendl J, Klingel K, Poller W, Schultheiss HP, Tschöpe C. Circulation. 2011 Nov 8;124(19):2082-93. doi: 10.1161/CIRCULATIONAHA.111.035964. Epub 2011 Oct 10.
  • Adiponectin is a negative regulator of antigen-activated T cells. Wilk S, Scheibenbogen C, Bauer S, Jenke A, Rother M, Guerreiro M, Kudernatsch R, Goerner N, Poller W, Elligsen-Merkel D, Utku N, Magrane J, Volk HD, Skurk C. Eur J Immunol. 2011 Aug;41(8):2323-32. doi: 10.1002/eji.201041349. Epub 2011 Jun 6.
  • Matricellular signaling molecule CCN1 attenuates experimental autoimmune myocarditis by acting as a novel immune cell migration modulator. Rother M, Krohn S, Kania G, Vanhoutte D, Eisenreich A, Wang X, Westermann D, Savvatis K, Dannemann N, Skurk C, Hilfiker-Kleiner D, Cathomen T, Fechner H, Rauch U, Schultheiss HP, Heymans S, Eriksson U, Scheibenbogen C, Poller W.
  • Circulation. 2010 Dec 21;122(25):2688-98. doi: 10.1161/CIRCULATIONAHA.110.945261. Epub 2010 Dec 6.
  • Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction.
  • Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher F, von Schlippenbach J, Skurk C, Steendijk P, Riad A, Poller W, Schultheiss HP, Tschöpe C. Circ Heart Fail. 2011 Jan;4(1):44-52. doi: 10.1161/CIRCHEARTFAILURE.109.931451. Epub 2010 Nov 12.
  • Description of a local cardiac adiponectin system and its deregulation in dilated cardiomyopathy. Skurk C, Wittchen F, Suckau L, Witt H, Noutsias M, Fechner H, Schultheiss HP, Poller W. Eur Heart J. 2008 May;29(9):1168-80. doi: 10.1093/eurheartj/ehn136. Epub 2008 Apr 3.
  • Alterations in myocardial tissue factor expression and cellular localization in dilated cardiomyopathy. Szotowski B, Goldin-Lang P, Antoniak S, Bogdanov VY, Pathirana D, Pauschinger M, Dörner A, Kuehl U, Coupland S, Nemerson Y, Hummel M, Poller W, Hetzer R, Schultheiss HP, Rauch U. J Am Coll Cardiol. 2005 Apr 5;45(7):1081-9. Erratum in: J Am Coll Cardiol. 2005 May 3;45(9):1561.

Koordination:

Prof. Dr. med. Wolfgang Poller

Leiter experimentelle Forschungsaktivitäten

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