Scientific Research Institutes > University Institutes > Pharmacology and Toxicology

Institute of Pharmacology and Toxicology

Director: Univ.-Prof. Dr. med. Antonio Sarikas

The Institute of Pharmacology and Toxicology is located at the Research and Teaching Building of Paracelsus Medical University in the heart of Salzburg. Our institute provides a state-of-the-art research infrastructure with modern lab space and research equipment to host an international team of research scientists and staff.

As a research institute we focus on translational medicine to elucidate disease mechanisms, to identify new drug targets and to develop novel therapeutic strategies. We use interdisciplinary approaches that include modern methods of molecular biology, protein biochemistry and mouse genetics to study the role of ubiquitin ligases and cell senescence in the context of cardiac hypertrophy and fibrosis. In addition, we screen and characterize gene mutations in patients with hereditary hearing loss in collaboration with the Department of Otolaryngology of Salzburg General Hospital (SALK).

The Institute of Pharmacology and Toxicology of Paracelsus Medical University is committed to excellence in teaching and training of medical and pharmacy students. We offer dedicated pharmacology teaching, ranging from lectures and award-winning e-learning tools to lab internships, bachelor, master or PhD theses.

Research

Ubiquitin-Proteasome-System in cardiac diseases

The Ubiquitin-Proteasome System (UPS) is a selective protein degradation pathway that is critically involved in the pathogenesis of several cardiac disorders. Central to the UPS is the recognition of a substrate by an E3 ubiquitin ligase, a step pivotal for the ubiquitin-mediated degradation of substrate proteins by the 26S proteasome. In the prototypic SCF (Skp1•CUL1•F-box protein•ROC1) complex, the CUL1 scaffold binds to the Skp1•F-box protein substrate-targeting module as well as to ROC1, which recruits E2 conjugating enzyme to catalyse the transfer of ubiquitin to the substrate protein (reviewed in Sarikas et al., 2011). F-box proteins are the variable components of the SCF type E3 ligases, which dictate the substrate specificity of the ubiquitin ligase. Of the 69 F-box proteins that are encoded by the human genome only a fraction has been studied in the heart (Spaich et al., 2012).

Our previous work has demonstrated a critical role of the UPS in the pathogenesis of hereditary hypertrophic cardiomyopathies (Sarikas et al., 2005; Vignier et al., 2009; Mearini et al., 2010; Schlossarek et al., 2012). Furthermore, we identified CRL7 as a novel regulator of the insulin and insulin like growth factor 1 (IGF-1) signalling pathway (Xu et al., 2008 and 2012; Scheufele et al., 2014, Hartmann et al., 2014).

In a siRNA library screening project funded by the German Centre for Cardiovascular Research (DZHK) we have recently identified several novel hypertrophy-modulating F-box proteins in the heart. By using modern methods of molecular biology, murine models of cardiac diseases and Cre/Lox knockout strategies we aim to further characterize the pathophysiological role of these ubiquitin ligases in the heart.

Key publications

Xu X, Sarikas A, Dias-Santagata DC, Dolios G, Lafontant PJ, Tsai SC, Zhu W, Nakajima H, Nakajima HO, Field LJ, Wang R, Pan ZQ. The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation. Mol Cell. 2008; 30: 403-414.

Xu X, Keshwani M, Meyer K, Sarikas A, Taylor S, Pan ZQ. Identification of the degradation determinants of insulin receptor substrate 1 for signaling cullin-RING E3 ubiquitin ligase 7- mediated ubiquitination. J Biol Chem. 2012; 287: 40758-40766.

Charron MJ, Pan ZQ, Engelhardt S, Sarikas A. Evidence for a regulatory role of Cullin-RING E3 ubiquitin ligase 7 in insulin signaling. Cell Signal. 2014; 26: 233-239.

Hartmann T, Xu X, Kronast M, Muehlich S, Meyer K, Zimmermann W, Hurwitz J, Pan ZQ, Engelhardt S, Sarikas A. Inhibition of Cullin-RING E3 ubiquitin ligase 7 by simian virus 40 large T antigen. Proc Natl Acad Sci U S A. 2014; 111: 3371-3376.

 

Role of premature senescence in cardiac diseases

Premature senescence is a tumorsuppressive mechanisms leading to p16INK4A or p53-mediated cell cycle arrest upon telomere shortening or oncogenic signaling. Recent studies have demonstrated an additional role for premature senescence in fibrogenesis of the liver and skin fibrosis (Krizhanovsky et al., 2008; Jun and Lau, 2010). Our lab currently studies the pathophysiological role of premature senescence in cardiac fibrosis and affected cell populations within the myocardium.

By using murine models of cardiac diseases (transaortic constriction (TAC) and Beta 1-adrenoreceptor (ADRB1) transgenic (Tg) model, respectively) and human heart biopsies, we demonstrated that cardiac fibroblasts (CF) undergo premature senescence in the course of fibrogenesis (Meyer et al. JACC 2016). Inactivation of the premature senescence program by genetic ablation of p53 and p16 INK4a (Trp53 -/- Cdkn2a -/- mice) resulted in aggravated fibrosis after TAC when compared to wild-type controls (49 ± 4.9% vs. 33 ± 2.7%, P < 0.01), and was associated with impaired cardiac function. Conversely, cardiac-specific expression of CCN1 (Cyr61), a potent inducer of premature senescence, by adeno-associated virus serotype 9 gene transfer, resulted in ~ 50% reduction of perivascular fibrosis after TAC when compared to mock- or dominant-negative CCN1-infected controls (11.9 ± 1.4% vs. 22.4±4.0% and 22.1±1.8%, respectively; P < 0.01), and improved cardiac function. Collectively, these data establish premature senescence as essential and novel anti-fibrotic mechanism and potential therapeutic target in the heart. In current research projects we aim to further characterize molecular mechanisms and contribution of myocardial microenviroment for senescence induction in the heart.

Key publication

Meyer K, Hodwin MS, Engelhardt, S, Sarikas A. Essential role for premature senescence of myofibroblasts in restraining cardiac fibrosis J Am Coll Cardiol. 2016;67:2018-2028.

 

Genetic and molecular determinants of hereditary hearing loss

Another main research focus of the Institute of Pharmacology and Toxicology is the understanding of genetic and molecular mechanisms of syndromic (Pendred syndrome) and non-syndromic malformative hearing loss. In collaboration with the Department of Otolaryngology at SALK (Prof. G. Rasp and Dr. S. Rösch) we have recruited the first Austrian cohort of patients with hearing loss associated with an enlarged vestibular aqueduct (EVA), one of the most common causes of sensorineural hearing loss (Roesch et al. 2018). The SLC26A4 gene, coding for the anion exchanger pendrin, is frequently mutated in the context of Pendred syndrome and non-syndromic EVA. Goal of the research is the precise understanding of the molecular derangements leading to loss of function of pathogenic variants of the pendrin protein, including structural alterations, cellular mis-localization, aberrant turnover and altered gene transcription (Pera and Dossena, PNAS 2008; Dossena et al. CPB 2011). The possible contribution of additional genes, including connexins GJB2, GJB3 and GJB6, as well as transcription factors, in determining malformative hearing loss is also investigated. Ultimate goal is to identify novel molecular targets, pathways and strategies for the development of future therapies for hearing loss.

The Institute of Pharmacology and Toxicology holds the approval for diagnostic gene analysis issued by the Bundesministerium für Arbeit, Soziales, Gesundheit und Konsumentenschutz, Austria (approval number: BMASGK-76120/0007-IX/B/16c/2018). The genes analyzed are GJB2, GJB6, SLC26A4 and POU3F4, all of which play a fundamental role in determining sensorineural hearing loss associated with malformations of the inner ear.

Key publications

Roesch, S; Bernardinelli, E; Nofziger, C; Tóth, M; Patsch, W; Rasp, G; Paulmichl, M; Dossena, S; Functional Testing of SLC26A4 Variants-Clinical and Molecular Analysis of a Cohort with Enlarged Vestibular Aqueduct from Austria. Int J Mol Sci. 2018; 19(1):

Pera A, Dossena S, Rodighiero S, Gandía M, Bottà G, Meyer G, Moreno F, Nofziger C, Hernández-Chico C, Paulmichl M. Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA. Proc Natl Acad Sci U S A. 2008;105:18608-18613.

Dossena S, Bizhanova A, Nofziger C, Bernardinelli E, Ramsauer J, Kopp P, Paulmichl M. Identification of allelic variants of pendrin (SLC26A4) with loss and gain of function. Cell Physiol Biochem. 2011;28:467-76.

 

Role of post-translational modifications of proteins in metabolic disorders

In this research project we aim to further elucidate the role of the posttranslational modification O-GlcNAcylation in metabolic diseases. O-GlcNAcylation is a specific type of O-glycosylation that controls protein function, stability, subcellular localization and interaction with molecular partners (Fisi et al, 2018). O-GlcNAcylation levels of cellular proteins are chronically elevated in various tissues of diabetic patients and in mice models of diabetes mellitus, and may contribute to the derangement of basic homeostatic functions, including the regulation of cellular volume, and to the progression of diabetic complications. Goal of the research is to identify the cellular functions that are controlled, and possibly, altered, by O-GlcNAcylation. Also, we aim to understand if O-GlcNAcylation and the cellular levels of the enzymes controlling O-GlcNAcylation may represent useful diagnostic markers for the early diagnosis and monitoring of progression of pre-diabetes, diabetes and diabetic complications.

Key publication

Fisi, V; Katai, E; Orban, J; Dossena, S; Miseta, A; Nagy, T. O-Linked N-Acetylglucosamine Transiently Elevates in HeLa Cells during Mitosis. MOLECULES. 2018; 23(6): 1275

 

New teaching media in medicine / Learning analytics

The Internet and the ubiquity of mobile devices open up new didactic opportunities for teaching in higher education. Using quantitative (surveys) and qualitative (focus groups, interviews) methods, we investigate the prevalence and use of digital learning media among today's students and their potential and limitations for knowledge acquisition and transfer. Another research focus is the collection, analysis and evaluation of digital data in the learning context (learning analytics). The goal is the evidence-based development of analysis algorithms in order to dynamically measure the level of knowledge and learning progress of students, to uncover potential problem areas and thus to contribute to the optimization of the teaching and learning process in pharmacology.

Key publications

Gutmann J, Kühbeck F, Berberat PO, Fischer MR, Engelhardt S, Sarikas A. Use of learning media by undergraduate medical students in pharmacology: a prospective cohort study. PLoS One. 2015;10:e0122624.

Kräenbring J, Monzon Penza T, Gutmann J, Muehlich S, Zolk O, Wojnowski L, Maas R, Engelhardt S, Sarikas A. Accuracy and completeness of drug information in wikipedia: a comparison with standard textbooks of pharmacology. PLoS One. 2014;9:e106930.

Kühbeck F, Engelhardt S, Sarikas A. OnlineTED.com - a novel web-based audience response system for higher education. A pilot study to evaluate user acceptance. GMS Z Med Ausbild. 2014; 31: Doc5.

Teaching

The Institute of Pharmacology and Toxicology of Paracelsus Medical University is committed to excellence in teaching and training of medical and pharmacy students. We offer some of the best pharmacology teaching, ranging from lectures and award-winning e-learning tools to lab internships, bachelor, master or PhD theses. 

In collaboration with the Technical University of Munich we have initiated and developed Pharmacases.de, an award-winning peer teaching and open access e-learning platform of pharmacology. Please visit Pharmacases.de for more information.

Prof. Sarikas and his team has developed OnlineTED, a web-based audience response system for higher education. Please visit onlineTED for further information.

Institute of Pharmacology and Toxicology participates in the following lectures and seminars at Paracelsus Medical University in Salzburg: 

Human Medicine diploma program

  • Lecture “Pharmacology and Toxicology”
  • Seminar and lecture “Scientific competence”

Bachelor`s degree study Pharmacy

  • Lecture “General Pharmacology A”
  • Lecture “General Pharmacology B”
  • Seminar “Pharmacovigilance”

Postgraduate doctorate study in Medical Science (PhD)

  • Lecture “Pharmacology”

Team and contact