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Brain disorders present a global debilitating burden to society urgently calling for in-depth molecular understanding of their pathological processes to propel the development of effective therapeutic targeting strategies forward. While many brain-localized aspects are known that regulate brain function, interestingly, a feature located nearly a meter away from the brain critically drives brain activity and cognition. This feature comprises the intestinal microbiota, or microbiome, which is considered to interact with the brain via the intestinal microbiome-gut-brain axis. Perturbations in the richness and diversity of the microbiome are a common feature in many brain-related disorders, including neurodegeneration, brain tumors, multiple sclerosis, autism spectrum disorders and schizophrenia. Nevertheless, the molecules, cell types and signaling pathways involved in this multi-tissue process remain enigmatic. Studies into this topic remain sparse as a result of multi-organ complexity and challenges to accurately recapitulate this complexity by means of current model systems of the human physiological microbiome-gut-brain axis. This project aims to provide fundamental mechanistic insights into how long distance interaction aids the communication between the microbiome and the brain health and disease by exploiting the differentiation potential of induced pluripotent stem cells into organoids. This project will generate an integrated microbiome-gut-brain axis from polycultured microbiome and stem cell-derived intestine, vagus nerve and brain connection that recapitulates key aspects of human physiology.
You will be generating human induced pluripotent stem cell-derived organoids of the intestine and vagus nerve along existing protocols. You will develop a differentiation procedure to create a brain stem organoid from pluripotent stem cells. Following their generation, you will validate the identity, stage of maturation, and functional activity of the organoids using biomarker (protein and mRNA) expression, imaging, epithelial barrier integrity and electrophysiological read-outs. Using CRISPR-Cas9-mediated gene editing you will modulate the genetic make-up of pluripotent stem cells to express potential features of interest to microbiome-gut-brain axis communication. Under the supervision of a highly skilled post-doctoral scientist and in collaboration with other groups at the University of Twente you will be creating microfluidic devices for organoid culture. You will generate bacterial cultures and use live cell stains to visualize their co-culture with intestinal organoids using microscopy. You will assess co-culture induced changes in specific marker expression using western blot, ELISA and confocal imaging.
University of Twente (UT)
We are seeking for a highly driven individual, keen to push the boundaries of current technological and biological state-of-the-art looking to pursue an academic career as a PhD
- You have a MSc degree in cell biology, biochemistry or neurobiology
- You have a hands-on in-depth expertise in (stem) cell biology and biochemistry
- You have affinity with neurobiological systems
- You preferably have experience using CRISPR-Cas9 to edict cell lines and worked with differentiation protocols to create organoid cultures before.
- You are an eloquent and transparent communicator, keen to learn from others and share your insights with the team
- Proficiency in English is required, both spoken and written
- You need to provide IELTS test results (minimum score 6.5) or TOEF iBT (minimum score 90)
- You are not shying away from leaving the beaten track to push our research forward, view challenges as exciting opportunities, and are an out-of -box thinker
- As some microfluidic chip fabrication will be required in this project, you are interested in learning how to create these devices.
- The latter is not necessary for native speakers of English or whose MSc program was in English.
Conditions of employment
- Fulltime position for four years
- The university offers a dynamic ecosystem with enthusiastic colleagues in a stimulating scientific environment.
- The PhD salary is € 2.541,- in the first year and increases to € 3.247,- in the fourth year.
- A holiday allowance of 8% of the gross annual salary and a year-end bonus of 8.3%.
- The number of holiday hours for full-time employment is 232 hours per calendar year.
- A personal development program within the Twente Graduate School.