PhD fellowship Deciphering the molecular pathogenesis of Cushing's disease (m/w/d)
Medizin I / Endokrinologie

The hypothalamic-pituitary-adrenocortical axis is activated during stress to maintain homeostasis in the body. In physiological conditions, secretion of hypothalamic corticotropin-releasing hormone is initiated by the CNS, which stimulates the anterior pituitary lobe of the pituitary to release ACTH. This in turn induces secretion of cortisol from the adrenal cortex, which itself exerts its effects by binding to intracellular glucocorticoid (GC) receptors that subsequently act as transcriptional regulators of GC responsive target genes. Cushing´s disease (CD) is a rare, but devastating endocrine disease resulting from chronic uncontrolled cortisol secretion caused by am ACTH-secreting pituitary adenoma. Patients suffer from increased morbidity (hypertension, diabetes mellitus etc.) and mortality. We identified deubiquitination as a major driver in CD (Reincke, Sbiera et al., Nature Genetics 2015 and Sbiera, et al. Neuro Oncology 2019). Ubiquitination, and its reverse process, deubiquitination, are the covalent attachment and, respectively, removal of the small protein modifier ubiquitin to and from a protein. Furthermore, these processes play an important role in proteasomal degradation and recycling but also in transcriptional regulation, protein trafficking and activation of kinases involved in intracellular signaling transduction.

For additional information just contact: sbiera_s(at)ukw.de or fassnacht_m(at)ukw.de

The successful candidate will utilize a combination of biomolecular and biochemical assays on tumor samples and cells lines to answer the following questions:

• Can we develop a human in vitro cell model to investigate the critical pathways identified in our project?
• What are the consequences of the key mutations on the anti-tumoral immune response and how can we exploit this to improve the therapeutic options for CD patients?
• Can we identify molecular therapeutic targets in aggressive CD adenomas using spatial molecular imaging and single cell sequencing?
  
   
  
  The applicant will have access to a very stimulating research environment as both a member of the prestigious Graduate School of Life Sciences of the University of Würzburg (http://www.graduateschools.uni-wuerzburg.de/life_sciences/) and as an associated member of the interdisciplinary DFG-funded collaborative research center 205 (https://adrenal-research.de). Furthermore, our group is one of the leading centres for the study of endocrine tumors with high ranking peer-reviewed publications (Beuschlein, et al. N Engl J Med 2014, PMID:24571724; Assié, et al., Nature Genetics 2014, PMID:24747642; Reincke, Sbiera et al., Nature Genetics 2015, PMID:5485838; Weigand, et al. Science Reports 2017, PMID:28250426; Sbiera, et al. Neur Ooncology 2019, PMID:31222332; Weigand, et al., Science Advances 2021, PMID:33608270).
  
   
  
  Applicants are invited from all nationalities, with a Master's degree in genetics, immunology or biochemistry/cell biology. Severely disabled persons will be given preference if they have essentially the same aptitude, qualifications and professional performance.
  
   
  
  Address applications (preferably by email as one pdf) to:
  
   
  
  PD Dr. Silviu Sbiera
  
  Dept. of Endocrinology and Diabetes
  
  University Hospital Würzburg
  
  Oberdürrbacher Str. 6
  
  97080 Würzburg
  
  Germany
  
  Email: sbiera_s(at)ukw.de​