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Medical Cell Research - C. Borner

Research interests

Medizinische Zellforschung - Research Interest
  Programmed cell death (PCD) and its predominant phenotype, apoptosis, is essential to ensure and maintain the life of multicellular organisms. If it is absent or dysregulated, embryogenesis is aborted or impaired, tissues homeostasis is interrupted and damaged or used-up cells are not disposed. Thus, defaults of apoptosis are implicated in numerous pathological conditions, ranging from degenerative disorders to autoimmunity and cancer. 
  Apoptosis can either be triggered by so called "death receptors" on the cell surface or by various forms of stress, such as a lack of cytokine/growth factor support and diverse types of cellular damage. These apoptotic stimuli provoke, in one way or the other, the activation of a set of previously inactive death proteases, the caspases, which, via an amplifying proteolytic cascade cleave hundreds of substrates to dismantle the cell. During periods of stress, the cell's decision to launch the cell death program relies primarily on the Bcl-2 family of proteins. This family consists of Bcl-2-like relatives that promote survival, and two structurally distinct relatives (Bax-like and BH3-only) which instead elicit cell death. Through protein-protein interactions, these opposing members integrate survival and death signals from the environment to determine whether to condemn the cell to its death demise or to endow it with the capacity to resist and survive.
  The last few years have seen an explosion of data implicating increased permeability of the outer mitochondrial membrane as an early step of intracellular death signalling. This mechanism allows apoptogenic factors such as cytochrome c to be released into the cytosol where they contribute to caspase activation. Because anti-apoptotic members of the Bcl-2 family prevent increased membrane permeability and protect cells from various death insults, it has been assumed that Bcl-2 family members primarily regulate mitochondrial integrity, and that loss of this integrity is the crucial commitment step to activate all relevant caspase activities. However, this view is about to change as recent findings have shown that apoptotic signalling can bypass mitochondria and even occur independently of caspase activation, but still be controlled by Bcl-2 family members. Thus, the Bcl-2 cohort must be capable of managing life-or-death decisions at several intracellular sites, via more than one mechanism and perhaps even in a cell-type specific manner.
  Because of their central role in regulating various types of apoptosis under physiological and pathological conditions, we would like to understand how the Bcl-2 family of proteins control both mitochondrial-dependent and -independent, as well as caspase-dependent and -independent death signaling pathways.
  We would like to achieve this goal as follows:
    1. Isolate proteins that interact with endogenous and overexpressed Bcl-xL, Bcl-2, Bax and Bak in healthy and apoptotic cells.
    2. Identify the mechanisms by which Bcl-xL, Bax and Bak are specifically targeted to mitochondria and how redistribution of Bax between the cytosol and mitochondria is regulated.
    3. Isolate components of caspase-independent death signaling which are controlled by Bcl-2 family members.
    4. Decipher the mechanisms by which the endoplasmatic reticulum (ER) contributes to apoptosis signaling.
    5. Understand the apoptotic signaling pathway induced by Semliki Forest and Sindbis alphaviruses.
    6. Isolate new survival factors by functional screens.
    7. Understand the molecular mechanisms of hepatocyte apoptosis and proliferation (BMBF HepatoSys, Systemsbiology regenerating hepatocytes) HepatoSys Homepage:


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