PhD studentship in Induced Pluripotent Stem Cell based models of the human Blood-Brain barrier PhD project

Number of awards:

1

Start date and duration:

January 2019 for 3 years.

Overview:

Therapeutic drugs readily exchange between the blood and the extracellular space of tissues with the exception of the barrier protected tissues The Blood Brain Barrier (BBB) is an example of this protection mechanism but it is also a major hurdle for the development neuro-therapeutics as it impedes passage of many therapeutic molecules into the CNS. Moreover, the BBB transport properties may be disrupted by diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis in addition to metabolic dysfunctions such as diabetes [1-5]. Thus, there is an urgent unmet need for a model of the human BBB that re-capitulates it’s in vivo characteristics in both healthy and diseased individuals.

This would be a valuable tool for the development of new therapeutics by identifying molecules that can be transported across the BBB and how their transport may be altered by disease states; the latter will be of particular value in designing potential drugs that will function in individuals with neurodegenerative or metabolic diseases. BBB function relies upon specialised molecular transport mechanisms in brain microvascular endothelial cells. These cells form tight intercellular junctions preventing the transfer of all but the smallest molecules. Selective transport employs solute carrier proteins or membrane receptors [6] and ATP binding cassette transporter proteins [7]. Other pathways exist for the translocation of larger molecules such as insulin (transcytosis) [8] while immune cells such as macrophages are able to cross by diapedesis [9] (see figure 1). In vitro models of bovine, mouse and rat BBB have been established, however interspecies differences with the human BBB compromise the utility of data from these models in human therapy development [10, 11]. Immortalized cell line-based BBB models suffer from a lack of mature barrier characteristics while primary ex vivo cells are difficult to obtain therefore this proposal aims to create human BBB models using cells generated from Induced Pluripotent Stem Cells (iPSC). Newcells Biotech is expert in the generation and differentiation of iPSC and as a member of StemBANCC, one the largest collection of iPSC in Europe, has access to any of the lines generated therein.

The student will therefore gain experience in the derivation of iPSC from primary tissue (peripheral blood, dermal fibroblasts) but will also differentiate iPSC from any of these sources into endothelial cells with phenotype similar to brain microvascular endothelial cells (BMEC), astrocytes, pericytes, neurons or oligodendrocytes, using state-of-the-art published protocols or methods developed in house. The iPSC derived endothelial cells will be characterised using transcriptomic analysis, immunocytochemistry and functional profiling of selective transporter proteins (in which Newcells has a competitive advantage owing to our ApproximateTM kidney proximal tubule transporter assay). The student will use iPSC derived cells to construct 3D BBB models from both control iPSC lines and those from patients with neurodegenerative diseases. These will be subjected to detailed analyses of barrier permeability and transporter protein activity in the presence/absence of drugs known to affect transporter function using protocols already available within the company [12-14].

Sponsor:

This project is part-funded by European Regional Development Fund.

Name of supervisor(s):

Professor Lyle Armstrong (https://bit.ly/2DVc8Q0), Institute of Genetic Medicine (https://bit.ly/2RpF1qv), Newcastle University (https://bit.ly/2zOzy5z).

Eligibility Criteria:

You must have at least a 2:1 BSc (Hons) in biomedicine, genetics, or a related area. A further qualification such as an MSc or MRes is advantageous.

How to apply

You must apply through the University’s online postgraduate application system. To do this please ‘Create a new account’ (https://bit.ly/2IAclXy).

Only mandatory fields need to be completed. However, you will need to include the following information:
•insert the programme code 8300F* in the programme of study section
•select PhD in the Faculty of Medical Sciences – Institute of Genetic Medicine Research’ as the programme of study
•insert the studentship code GM009 in the studentship/partnership reference field
•attach a covering letter and CV. The covering letter must state the title of the studentship, quote the studentship reference code GM009 and state how your interests and experience relate to the project
•attach degree transcripts and certificates and, if English is not your first language, a copy of your English language qualifications.

Contact:

For further details, please contact:

Professor Lyle Armstrong (https://bit.ly/2DVc8Q0)
Institute of Genetic Medicine (https://bit.ly/2RpF1qv)
Newcastle University (https://bit.ly/2zOzy5z)
The International Centre for Life
Central Parkway
Newcastle upon Tyne. NE1 3BZ
Email: [Email Address Removed]