Thinking of doing your PhD in the Life Sciences? The International PhD Programme (IPP) Mainz is offering talented scientists the chance to work on cutting edge research projects within the open call on “Molecular Mechanisms in Genome Stability & Gene Regulation”. As an IPP PhD student, you will join a community of exceptional scientists working on diverse topics ranging from how organisms age or how our DNA is repaired, to how epigenetics regulates cellular identity or neural memory. The research group of Dorothee Dormann offers the following PhD project:

In the Dormann lab, we study how RNA-binding proteins (RBPs), such as TDP-43, FUS or TAF15, become dysfunctional in diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer’s disease (AD). These RBPs function in various RNA metabolic pathways, including the regulation of transcription, pre-mRNA splicing, mRNA stability and translation as well as in DNA damage repair. A subset of patients with ALS, FTD and AD present pathological cytoplasmic redistribution and aggregation of TDP-43, FUS or TAF15, however it is still not well understood how these proteins become mislocalized and aggregated in disease and how RBP aggregation causes a decline in cellular function and eventually neurodegeneration.

PhD project: Role of cellular mechanical stress in RNA-binding protein aggregation diseases

We and others previously showed that different types of cellular stress, e.g. oxidative stress or heat shock, elicit recruitment of RBPs into stress granules (SGs) and that SGs and aberrant phase transitions can lead to pathological TDP-43 or FUS aggregation. In this project, we now want to focus on mechanical stress and investigate how it impacts RBP mislocalization and aggregation. We will apply mechanical stress, e.g. through mechanical agitation or by applying shear forces in microfluidic devices, and will investigate how this impacts phase separation and aggregation of TDP-43, FUS or TAF15 in vitro. We will also apply mechanical stress to cells and will investigate how (in comparison to other cellular stressors) it impacts nucleocytoplasmic transport and the formation of SGs, and hence cytoplasmic mislocalization and aggregation of RBPs, such as TDP-43, FUS or TAF15. We also seek to investigate how the presence of aggregates in cells impacts the mechanical properties of cells, e.g. changes to the viscoelasticity of the cytoplasm and/or nuclear shape.

To address these questions, we will use recombinant proteins to study phase separation/aggregation in vitro, e.g. with microscopic or biophysical assays, as well as cell lines and neuronal cell culture models to study the intracellular RBP behaviour using diverse imaging techniques (e.g. confocal microscopy, live cell imaging) combined with biochemical and cell biological methods or proteomics.
The PhD project is part of the EU-funded doctoral training network “NEUROMECH”, which seeks to characterize the role of mechanobiology in the pathogenesis of neurodegenerative diseases. Investigators in the consortium have expertise in mechanobiology, neurodegeneration, DNA damage, neuropathology, medical imaging and big data analysis. Students will profit from lab exchanges and diverse training activities within the NEUROMECH network.

If you are interested in this project, please select Dormann as your group preference in the IPP application platform. Are you an ambitious scientist looking to push the boundaries of research while interacting with colleagues from multiple disciplines and cultures? Then joining the IPP is your opportunity to give your scientific career a flying start!
All you need is:

Master or equivalent
Interactive personality & good command of English
2 letters of reference
We offer

Exciting, interdisciplinary projects in a lively international environment, with English as our working language

Advanced training in scientific techniques and professional skills
Access to our state-...