About the Project
Project: In year 1 we will generate induced pluripotent stem cells (iPSCs) through patient samples and state-of-the-art technologies such as the CRISPR-Cas9 system. We will differentiate the disease and control iPSCs into cortical neurons and study their characteristics in detail. Dr Banka led the identification of the KMT2C-disorder, has a large cohort of patients with this new condition and has previously used CRISPR-Cas9 to study mechanisms of several genetic conditions. Prof Kimber is an expert in using and differentiating stem cells for understanding human diseases.
In year 2 we will employ advanced techniques such as single-cell ATAC-Seq, bulk RNA-Seq and ChIP-Seq at different stages of differentiation to understand the mechanisms behind the abnormalities observed in the iPSC-derived neurons. Prof Sharrocks is an epigenomics expert and routinely uses such techniques in the context of human diseases. We will use advanced systems biology approaches for multi-omics data integration. Dr Stevens has extensive experience in using both data-driven and hypothesis-free approaches for analysis of multi-omics data.
In the final year we will test a selection of drugs to attempt phenotype rescue in our cell models.
Outcome: The project will lead to identification of mechanism underlying a novel human neurodevelopmental syndrome and pave the way to possible future clinical trials.
The student will benefit from being supervised by an inter-disciplinary team of basic scientists and a clinical academic with complementary areas of expertise. This will expose the student to a breadth and depth of biomedical research that is usually very difficult to find in a project set in a single laboratory.
The skills learnt in the project are likely to be in high demand for several years in biological and medical sciences. The project will provide a solid foundation in understanding disease mechanisms and development of new treatments.
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a relevant area / subject. Candidates with experience in working with stem cells or CRISPR-Cas9 with an interest in using large datasets to study rare diseases are encouraged to apply.
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select PhD Genetics
For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk
As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit
Bjornsson, H. T. et al. Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome. Science Translational Medicine 6, 256ra135-256ra135 (2014).
Benjamin, J. S. et al. A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome. PNAS 114, 125–130 (2017).
Tsai, I.-C. et al. Small molecule inhibition of RAS/MAPK signaling ameliorates developmental pathologies of Kabuki Syndrome. Scientific Reports 8, 10779 (2018).
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