University of Bristol, UK. School of Clinical Sciences
Marie Curie Early Stage Researcher/3 Year PhD studentship
Developing neurobiology/stem cell biology
Maintenance/Salary £39,649 to £45,941 p.a until Oct-Dec 2016
Applications are invited for a Marie Curie early stage researcher including those who wish to do a PhD at Bristol University. They should satisfy the eligibility requirements that apply to all Marie Curie Early Stage Researchers: At the time of recruitment, applicants should not hold a PhD or have more than 4 years’ research experience (FTE) after graduation and should not have resided in the UK for more than 12 of the 36 months immediately before appointment.
Until now it has been assumed that teratogens will damage a baby directly, by passing from the maternal blood, through the placenta and into the foetal circulation. We have discovered that this may not necessarily be so. In two papers published in Nature Nanotechnology we have demonstrated an indirect mechanism. In these experiments an established model barrier of the human placenta, a bilayered cell barrier of BeWo cells, a choriocarcinoma cell line, was grown on transwell inserts. The cell barrier was exposed to CoCr nanoparticles, metal ions, altered oxygen or drugs that initiate mitochondrial free radicals. This exposure set up a process of cell to cell signalling through connexin and pannexin channels within the cell barrier. This in turn stimulated a release of factors that caused DNA damage and chromosome aberrations in human fibroblasts or stem cells on the other side and also led to a secretion of cytokines and chemokines. Importantly the nanoparticles, ions or drugs did not pass through the barrier. We now wish to focus on two key aspects of this research. Firstly we wish to improve the cell barrier to make it a more faithful replica of the actual placenta. To do this we will isolate primary trophoblasts from human placenta and use them to make bilayered and monolayered barriers with and without syncytialisation.
A second feature of this research will be to explore the mechanism and actions of the signalling. Taking DNA damage chromosomal aberrations and cytokine secretion as our endpoints, we will explore the role of connexins, pannexins and purinergic transmission in
the primary cell barrier signalling. We will use nanoparticles to modify or prevent this signalling. We will explore whether cells on the other side of the barrier may be modified by nanoparticle treatment of the barrier. In the long term our aim is to explore whether it would be possible to reduce fetal damage in utero through a treatment of the placenta.
The applicant will assay the release of different molecules from the barrier and then examine their effect on various cell types including human embryonic stem cells and developing neurones. This is a multidisciplinary investigation with direct implications to human biology and disease.
Applicants should send their c.v. to c.p.case@bristol.ac.uk
Sood, et al C.P. Case Signalling of DNA damage and cytokines across cell barriers exposed to nanoparticles depends on barrier thickness Nature Nanotechnology 6, 824–833 (2011)
Bhabra G,et al Case CP. Nanoparticles can cause DNA damage across a cellular barrier.Nature Nanotechnology.;4:876-83 (2009).
