Aging related pathomechanisms in cancer

Institute of Nutrition Sciences

M. Ristow, M. Glei

Fritz-Lipmann Institute

Z. Q. Wang, M. Platzer

Hans-Knöll Institut

H. P. Saluz, F. Hähnel

Chromosomal instability analysis and targeting

Questions:

• How do mice with genetically modified genes involved in cellular response to DNA damage and cell cycle control respond to to genotoxic stress and spontaneous or induced carcinogenesis?
• What is the role of fragile sites in chromosomal instability syndromes and cancer?
• Which mechanisms mediate the decline of nuclear protein maintenance in senescent cells and how does it affect DNA damage repair and chromosomal instability?
• Are specific types of aneuploidy and centrosome amplification biomarker for tumor progression and response to therapy?

Autophagy in cancer biology and chemotherapy

Questions:

• What is the mechanism of tumor suppression by GABARAP as a gene being involved in phagocytosis?
• Does induction and subsequent blocking of autophagy affect the induction of apoptosis and the effectiveness of chemotherapy?
• What is the role of autophagy in cellular stress response and DNA damage induced by cancer therapy?
• Is there an age related decrease of the therapy associated induction of autophagy?
• Is cellular senescence a result of decreased cellular repair?

• List of project drafts of principal investigators (PI) with external research funding (6x DFG, 4x BMBF, 2x EU, 2x German Cancer Aid, 2x DAAD, 1x Finland Academy, 1x Stefan Morsch foundation) and publication track records (see below)
• Established interactions between the different research groups at the Jena University Hospital (JUH)1, Leibniz Institute for age research (Fritz-Lipmann-Institute, FLI)2 and other faculties of the Friedrich-Schiller-University (FSU)
• Profound willingness to share the well developed lab infrastructure, methods, models and resources

Expertise (I)

• Mouse models for chromosomal instability and phagocytosis
• Induction of genotoxic stress and chemical carcinogenicity
• Induction and analysis of autophagy in rodents and humans
• Surgery of rodents (especially partial hepatectomy)
• Availability of various established senescence models, tumor cell lines and genetically modified cell lines
• Advanced cancer cytogenetics and molecular cytogenetics methods

Expertise (II)

• In situ biomarker analysis
• DNA ploidy analysis
• Digital slide microscopy and image analysis
• Monitoring senescence and autophagy after drug treatment in vitro
• Protein analysis in different cellular compartments
• Proteasome research
• Histopathology and cytology

* Stolz A, Ertych N, Kienitz A, Vogel C, Schneider V, Fritz B, Jacob R, Dittmar G, Weichert W, Petersen I, Bastians H. The CHK2-BRCA1 tumour suppressor pathway ensures chromosomal stability in human somatic cells. Nat Cell Biol. 2010;12(5):492-9.

* Saidi A, Li T, Weih F, Concannon P, Wang ZQ. Dual functions of Nbs1 in the repair of DNA breaks and proliferation ensure proper V(D)J recombination and T cell development. Mol Cell Biol. 2010 Oct 4.

* Schmidt U, Wollmann Y, Franke C, Grosse F, Saluz HP, Hänel F. Characterization of the interaction between the human DNA topoisomerase IIbeta-binding protein 1 (TopBP1) and the cell division cycle 45 (Cdc45) protein. Biochem J. 2008;409(1):169-77.

* Thierbach R, Drewes G, Fußer M, Voigt A, Kuhlow D, Blume U, Schulz TJ, Reiche C, Glatt H, Epe B, Steinberg P, Ristow M. The Friedreich's Ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals. Biochem J. 2010 Sep 6. [Epub ahead of print]

* Glei M, Hovhannisyan G, Pool-Zobel BL. Use of Comet-FISH in the study of DNA damage and repair: review. Mutat Res. 2009;681(1):33-43.