Dr. Martin Graef

Research Area: Autophagy and Cellular Ageing

Website:  http://cecad.uni-koeln.de/Dr-Martin-Graef.447.0.html

1. Research Background:

Cells have evolved complex homeostasis and quality control systems to cope with metabolic and diverse stress challenges. One of these central systems is the evolutionarily highly conserved process termed “autophagy”. Autophagy allows cells the basal and inducible turnover of intracellular components ranging from whole dysfunctional organelles, e.g. mitochondria, to protein aggregates. Defects in autophagy are associated with ageing and age-associated diseases including neurodegeneration, metabolic disease, or cancer.  A hallmark of (macro-) autophagy is de novo formation of autophagosomes, double-membrane vesicles, which, driven by the concerted action of a complex core autophagy machinery and a number of other cellular processes, encapsulate cytoplasmic cargoes of diverse size and nature and target them for lysosomal or vacuolar degradation and recycling. Cells have to carefully fine-tune the level of autophagy according to current needs.

2. Research questions addresses by the group:

In our group, we address outstanding fundamental questions regarding (1) how and where autophagomes form, (2) how cells communicate metabolic and functional information to regulate autophagy, (3) what cellular functions support full regulatory capacity, and (4) how cellular dysfunction accumulating during ageing or disease affects autophagy.  In addition, we are exploring the cellular mechanisms of ageing. Eukaryotic cells undergo only a limited number of mitotic cell divisions. Using synthetic biology approaches in yeast, we have established unique tools to explore the genetic and metabolic principles underlying mitotic ageing on system-wide scale.

3. Possible projects:

Available projects generally depend on the interests of the applicant and will be discussed in person, but might cover:

  1. exploring mechanisms of autophagosome biogenesis
  2. Interdependent communication of autophagy and cell metabolism
  3. "Resetting the ageing clock: analysis of meiotic rejuvenation"

Budding yeast cells divide asymmetrically and generate an ageing mother and a young daughter cell. As virtually all eukaryotic cells, mother cells undergo a limited number of cell divisions (20-30) before entering senescence, a phenomenon called replicative or mitotic ageing. With increasing cell divisions, mother cells show evolutionarily conserved signs of aging including loss of mitochondrial and vacuolar/lysosomal function, accumulation of protein damage and aggregates, and nucleolar changes. Remarkably, inducing meiosis, the process required for spore formation in yeast or gametogenesis in multicellular organisms, in aged mother cells cures all aging features and emerging spores/gametocytes show full replicative potential. We have developed unique tools to start to characterize the underlying mechanisms of meiotic rejuvenation, which likely will have broad and fundamental implications in understanding ageing and rejuvenation mechanisms.

Goals are:

  • (a) Determining the rejuvenation potential of different stages of the meiosis program
  • (b) System-wide identification and analysis of the meiotic rejuvenation machinery

4. Applied Methods and model organisms:

We use Saccharomyces cerevisiae and mammalian cell culture systems including haploid mouse stem cells and employ state-of-the-art, interdisciplinary approaches ranging from biochemistry, genetics, fluorescence microscopy, synthetic biology to system-wide analyses including whole proteome profiling, protein interaction networks and high-throughput flow-cytometry. We have established a number of fully automated systems encompassing robotic systems for genetic screening, liquid handling, growth profiling, flow-cytometry, and bioinformatic pipelines to profile autophagy and mitotic ageing in genetic and metabolic space.