Haendeler research group: Heisenberg-group - environmentally-induced cardiovascular degeneration

Head of research group:
Univ.-Prof. Dr. rer. nat. Jojo (Judith) Haendeler, Heisenberg-Professor tl_files/bilder/mail.gif
Phone: +49 (0)211-3389-291

Core Unit leader:
Priv.-Doz. Dr. rer. nat. Yogi (Joachim) Altschmied, S2 lab tl_files/bilder/mail.gif
Dr. rer. nat. Sabine Metzger, mass spectrometry tl_files/bilder/mail.gif

Postdocs:
Dr. rer. nat. Nilo Ale-Agha tl_files/bilder/mail.gif
Dr. rer. nat. Karin Aufenvenne tl_files/bilder/mail.gif
Dr. rer. nat. Nadine Dyballa-Rukes tl_files/bilder/mail.gif
Dr. rer. nat. Stefanie Kohlgrüber tl_files/bilder/mail.gif

PhD students
:
Philipp Jakobs, MSc (scholar) tl_files/bilder/mail.gif
Kirsten Jander, MSc (scholar) tl_files/bilder/mail.gif
Mark Zurek, cand. med. (scholar)

Technical assistance:
Christine Goy, lab manager tl_files/bilder/mail.gif
Olaf Eckermann, deputy lab manager tl_files/bilder/mail.gif
Florian von Ameln, BTA tl_files/bilder/mail.gif

Research profile

The major focus of the Haendeler research group is to elucidate environmentally induced molecular mechanisms of aging processes and age-associated diseases of the cardiovascular and cardiopulmonary system. Within this context we work on the following four subprojects:

1. the function and regulation of Telomerase Reverse Transcriptase (TERT) in the nucleus and in the mitochondria ex vivo and in vivo,

2. the regulation of Thioredoxin (Trx-1), identification of new binding partners of Trx-1 and their functions in the cardiovascular system,

3. the function and regulation of transcription factors, especially Grainyhead-like 3 (GRHL3) and Arylhydrocarbon Receptor (AhR), in the cardiovascular system,

4. the impact of exercise, diet and carbon nanoparticles on the cardiovascular and cardio-pulmonary system.

Projects

One aspect of the subproject 1 is to elucidate the regulation and function of Telomerase Reverse Transcriptase (TERT) by extrinsic factors. Of special interest are the underlying molecular mechanisms leading to nuclear export of TERT, which results in accelerated cellular senescence and organismal aging. This research was and is funded by the Deutsche Forschungsgemeinschaft (HA2868/2-3; HA2868/6-1). Another aspect in the subproject 1 is to investigate the functional role of mitochondrially localized TERT in aging processes and age-associated diseases. This research topic is of special interest not only for cardiovascular and cardiopulmonary aging processes but also for extrinsic skin aging. To analyze the organelle specific functions of TERT in more detail, the Haendeler research group generated cells and mice, which exclusively contain TERT either in the nucleus or in the mitochondria. With these unique cells and mice, we can for the first time determine the impact of TERT in the respective organelle and thus the potential consequences for preventive strategies. This research was and is funded by the Deutsche Forschungsgemeinschaft (HA2868/6-1; HA2868/9-1; AL288/2-1; SFB728 TPB5).

The subproject 2 „regulation of Thioredoxin-1 (Trx-1) in endothelial cells“ deals with the regulation of the oxidoreductase Trx-1 by environmentally-induced reactive oxygen species. Another aspect of this subproject is to investigate the role of the multiple known and unknown interaction partners of Trx-1 in the cytosol as well as in the nucleus in vascular functions. Moreover, preliminary data suggest that carbon nanoparticles reduce Trx-1 protein levels in vascular endothelial cells and in lung epithelial cells (cooperation with the Krutmann/Unfried research group). Therefore, the long-term goal is to determine whether human Trx-1 can be used as a therapeutic. First results demonstrated that treatment of dermal fibroblasts with Trx-1 protects from UV-induced cellular changes. All these aspects of subproject 2 were and are funded by the Forschungskommission of the Heinrich Heine University Duesseldorf and by the Deutsche Forschungsgemeinschaft (HA2868/3-2; HA2868/3-3; IRTG1902 TP2).

Within subproject 3 "Function and regulation of transcription factors, especially Grainyhead-like 3 (GRHL3) and Arylhydrocarbon Receptor (AhR), in the cardiovascular system" the role of these transcription factors in the changed endothelial function triggered by external factors is analyzed ex vivo and in vivo. One critical mediator of endothelial and thus vessel function is nitric oxide (NO), the levels of which are substantially influenced by the aging process and environmental conditions. As GRHL3 and AhR have an opposite impact on NO-bioavailability, the major focus of this subproject is the definition and detailed characterization of the regulatory networks in which these two transcription factors are embedded. The long-term goal is the identification of points of intervention, which would allow to maintain or even improve vessel functions. This research was and is funded by the Forschungskommission of the Heinrich Heine University Duesseldorf and the Deutsche Forschungsgemeinschaft (GRK1089; GRK1033 TP3; IRTG1902 TP1).

One aspect of subproject 4 deals with the protective effects of mitochondrially localized proteins in the sub-acute phase after myocardial infarction. Another focus is the effect of coffee drinking/caffeine on the cardiovascular system ex vivo and in vivo and the influence of voluntary running after myocardial infarction on telomerase and the mitochondria. All these projects are directly or indirectly concerned with preventive molecular mechanisms. These projects were and are supported through local joint research consortia with the Heinrich Heine University Duesseldorf funded by the Deutsche Forschungsgemeinschaft as well as by trans-regional cooperations with the Saarland University Hospital and the Charité Berlin (SFB 612; SFB 1116; Förderung des Saarlandes; Corona Stiftung). Furthermore, within subproject 4 molecular mechanisms of cardiovascular diseases are analyzed. In this context, particularly the relevance of reactive oxygen and nitrogen species for age-induced dysfunction of the cardiovascular system is investigated. The overall goal is the development of innovative molecular prevention strategies, with which age- and environment-dependent disturbances of cardiovascular functions could be avoided. This line of research is funded by the Leducq Foundation Transatlantic Network of Excellence and the Deutsche Forschungsgemeinschaft (DO602/9-1). Another aspect of subproject 4 is a collaborative research project with the Krutmann/Unfried research group investigating the role of carbon nanoparticles in cardiovascular and cardiopulmonary aging processes ex vivo and in vivo. The long-term goal of this research is to elucidate the molecular mechanisms induced by carbon nanoparticles in the lung and vessels, and subsequently to develop innovative preventive strategies to counteract this unavoidable, environmental burden. This research was and is funded by the Deutsche Forschungsgemeinschaft (HA2868/6-1; HA2868/11-1; UN110/4-1).

Service

The Haendeler lab is in charge of the core units BSL2 laboratory Gurlittstr (head: Joachim Altschmied, PhD), mass spectrometry (head: Sabine Metzger, PhD; Junior PI: Nadine Dyballa-Rukes, PhD) and fluorescence microscopy Gurlittstr (Nilo Ale-Agha, PhD).

Cooperations

IUF internal: Krutmann research group/team Unfried; Esser research group; Haarmann-Stemmann junior research group; Ventura liaison research group.

National: Prof. Kelm, Prof. Goedecke, Prof. Boege, Prof. Martin, Prof. Schaal, Heinrich Heine University Duesseldorf; Prof. Rassaf, University Hospital Essen; Prof. Laufs, Prof. Maack, Saarland University Hospital; Prof. Doenst, University Hospital Jena; Prof. Klotz, University of Jena; Prof. Endres, Charité Berlin.

International: Prof. Gnaiger, University of Innsbruck, Austria; Dr. Saretzki, Newcastle University, Newcastle upon Tyne, UK; Prof. Shah, Kings College London, UK; Prof. Kass, Johns Hopkins University, Baltimore, USA; Prof. Leitinger, Prof. McNamara, University of Virginia, Charlottesville, USA, Prof. Winkler, National University of Singapore-

Selected publications

Farrokh S*, Brillen A-L*, Haendeler J, Altschmied J#, Schaal H#: Critical regulators of endothelial cell functions: for a change being alternative. Antioxid Redox Signal 22(14): 1209-1211, 2015. (*,# equal contribution) [pubmed]

Haendeler J, Mlynek A, Büchner N, Lukosz M, Graf M, Güttler C, Jakob S, Farrokh S, Kunze K, Goy C, Guardiola-Serrano F, Schaal H, Cortese-Krott M, Deenen R, Köhrer K, Winkler C, Altschmied J: Two isoforms of Sister-of-Mammalian-Grainyhead have opposing functions in endothelial cells and in vivo. Arterioscler Thromb Vasc Biol 33(7): 1639-1646, 2013. [pubmed]

Zschauer T-C, Kunze K, Jakob S, Haendeler J*, Altschmied J*: Oxidative stress induced degradation of Thioredoxin-1 and apoptosis is inhibited by Thioredoxin-1/actin interaction in endothelial cells. Arterioscler Thromb Vasc Biol, 31(3): 650-656, 2011. (* equal contribution) [pubmed]

Büchner N*, Altschmied J*, Jakob S, Saretzki G, Haendeler J: Well-known signalling proteins with new functions in the nucleus and mitochondria. Antioxid Redox Signal 13(4): 551-558, 2010.(* equal contribution) [pubmed]

Werner C, Fürster T, Widmann T, Pöss J, Roggia C, Hanhoun M, Scharhag J, Büchner N, Meyer T, Kindermann W, Haendeler J, Böhm M, Laufs U: Physical exercise prevents cellular senescence in circulating leukocytes and in the vessel wall. Circulation 120(34): 2438-2447, 2009. [pubmed] (open access)

Haendeler J, Hoffmann J, Tischler V, Berk BC, Zeiher AM, Dimmeler S: Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69. Nat Cell Biol 4(10): 743-749, 2002. [pubmed]