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Molecular Biology of Cell Growth

Our lab studies the regulation of cellular growth under physiological and pathological conditions. The predominant form of growth of cardiomyocytes postnatally is increase in cell size (hypertrophy), not number. Many stimuli that provoke hypertrophic growth of cardiomyocytes involve the same signaling molecules known to be involved in proliferation and oncogenic transformation. Furthermore, chronic cardiovascular stresses, such as arterial hypertension or myocardial infarction, result in pathological growth associated with decreased cardiac function, ventricular remodeling, and, ultimately, heart failure. Our goal is to characterize key pathways of pathological remodeling in order to identify novel targets for the treatment of chronic heart failure.

Specific projects include the role of the mTOR complex in the myocardium. Signals from growth factors, nutrients, energy status, as well as many stressors impinge upon the mechanistic target of rapamycin (mTOR), which exists in 2 distinct complexes, mTORC1 and mTORC2. Proline Rich AKT Substrate of 40 kDa (PRAS40) is a specific component of mTORC1. PRAS40 blocks cellular growth in myocytes by inhibition of mTORC1 and our recent results demonstrate that PRAS40 is a potent and critical mediator of cardioprotection. Therefore, mTORC1 inhibition by PRAS40 represents a potentially important target in the treatment of pathological remodeling. Using novel animal models, we plan to understand how mTORC1 activity is regulated in cardiac physiology and pathology. Although the mechanisms that regulate mTORC1 are well understood, the regulation of mTORC2 is relatively poorly characterized.

Genetic deletion of mTORC2 is associated with increased ischemic damage after myocardial infarction.  Using in vivo mouse and cell culture models, we aim to identify the regulatory pathways and interaction partners of mTORC2 and thereby better understand their role in the regulation of cardiac growth and metabolism. We seek to identify ways to increase mTORC2 signaling, since correctly timed inhibition of mTORC1 in conjunction with mTORC2 potentiation could be a potent combinatorial approach to blunt cellular losses and to ameliorate the progression of degenerative changes accompanying ischemic damage.

In addition we study the role of calcium in cellular growth in myocytes. Altered calcium-signaling plays an important role in the pathophysiology of cardiac diseases such as myocardial infarction and pathological hypertrophy. Ca2+-release-activated Ca2+ entry (CRAC) is an established mechanism for non-excitable cells to replenish intracellular calcium stores and for subsequent Ca2+-dependent signaling cascades. The role of novel CRAC regulating proteins in cardiomyocytes will be elucidated by gene repression and overexpression techniques.

Team

Masterstudentin

  • Carolyn Schneider

Auszubildende

  • Candelas Groß Valle

Collaborators

Universität Heidelberg


Dr. Shirin Doroudgar
Prof. Christoph Diederich
Prof. Dr. Bernd Bukau
Prof. Dr. Johannes Backs
Dr. Mathias Konstandin

National

Prof. Dr. Oliver Friedrich, Universität Erlangen

International

Prof. Dr. Mark Sussman, San Diego State University Heart Institute, San Diego, California, USA
Prof. Dr. Chris Glembotski, San Diego State University Heart Institute, San Diego, California, USA

Vacancies - Jobs and Doctoral Theses

We regularly seek highly motivated candidates. Please contact Mr. Völkers (head of research group) or Lonny Jürgensen (Lab manager/Research technician).

AG Völkers

Belongs to Klinik für Kardiologie, Angiologie, Pneumologie
Contact
Im Neuenheimer Feld 669
69120 Heidelberg
Directions


06221 56-8319

More details

Awards & Funding

Awards
  • 2009-11 DFG-Forschungsstipendium
  • Adumed Forschungspreis 2010
  • Joachim Siebeneicher Promotionspreis der Universität Heidelberg 2009
  • Ludolf-Krehl Preis der Südwestdeutschen Gesellschaft für Innere Medizin 2007
  • Young Investigator Award der Deutschen Gesellschaft für Innere Medizin  2004
Funding

Emmy Noether Program 
Eliteprogamm Baden Württemberg Stiftung
Deutsches Zentrum für Herz-Kreislauf-Forschung 
Klinik für Kardiologie, Angiologie und Pneumologie der Universitätsklinik Heidelberg