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Development of iPSCs from patients with Urofacial Syndrome for disease modelling


Faculty of Biology, Medicine and Health

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Prof S J Kimber , Prof A Woolf Applications accepted all year round Self-Funded PhD Students Only

About the Project

Peripheral neuropathies (PNs) affect 2% of the general population. Somatic PNs cause locomotor and sensory deficits, while autonomic PNs cause cardiac dysrhythmias and gastrointestinal and urinary bladder dysfunction. Despite that facts that PNs are, as a group, common and they cause considerable morbidity, specific treatments to cure or ameliorate them are lacking. PNs have varied aetiologies, including environmental and genetic. An example of the latter is the urofacial syndrome (UFS), and this motor and autonomic neuropathy can be used as a model for novel biological therapies.

UFS pathobiology and therapies will act as paradigms for commoner PNs, including those which occur in type 1 diabetes mellitus. One approach to this is to develop disease models for the neural element of UFS by making induced pluripotent stem cells (iPSCS) from somatic cells of patients with specified genetic mutations leading to UFS and differentiate these to relevant neuronal subtypes. In this project the student will optimise a neural differentiation protocol already developed in the lab from published protocols for neurepithelium and motor neurons.

The student will characterise wild type human iPSCS and hESCs differentiated to neurons and establish the range of phenotypes obtained from different genetic back grounds. He/she will compare UFS iPSCs (HPSE2 and LRIG2 mutations) differentiated to neurons with wild type iPSCs and hESCs and where possible this will include iPSCs from unaffected siblings. In collaboration with postdoctoral researchers he/she will correct the mutation using gene editing technologies to produce a generically matched iPSC control.

The research will be extended to use biochemical correction techniques potentially leading to new drug discovery if time allows. Techniques include pluripotent stem cell (PSP) culture, iPSP derivation and characterization by immunocytochemistry flow cytometry Q-PCR and embryoid body analysis. Western blotting, electophysiological neuron analysis, gene editing technologies.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum 2:1 (or equivalent) in a related area / subject. 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.

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 www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (https://www.bmh.manchester.ac.uk/study/research/fees/). 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/).

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.

References

Daly SB, Urquhart JE, Hilton E, McKenzie EA, Kammerer RA, Lewis M, Kerr B, Stuart H, Donnai D, Long DA, Burgu B, Aydogdu O, Derbent M, Garcia-Minaur S, Reardon W, Gener B, Shalev S, Smith R, Woolf AS, Black GC, Newman WG. Mutations in HPSE2 cause urofacial syndrome. Am J Hum Genet 11:963-969, 2010.

McKay TR, Camarasa MV, Iskender B, Ye J, Bates N, Miller D, Fitzsimmons JC, Foxler D, Mee M, Sharp TV, Aplin J, Brison DR, Kimber SJ. Human feeder cell line for derivation and culture of hESc/hiPSc. Stem Cell Res 7:154-162, 2011.

Newman WG, Woolf AS, Stuart HM. Urofacial Syndrome. In: Pagon RA, Adam MP, Bird TD, et al, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013. http://www.ncbi.nlm.nih.gov/books/NBK154138/

Stuart HM, Roberts NA, Bergu B, Daly SB, Urquhart JE, Bhaskar S, Dickerson J, Mermerkaya M, Silay MS, Lewis MA, Olondriz BO, Gener B, Beetz C, Varga RE, Gülpinar O, Süer E, Yalçinkaya F, Gücük A, Yue WW, Erdogan F, Berry A, Hanley NA, McKenzie EA, Hilton EN, Woolf AS, Newman WG. LRIG2 mutations cause urofacial syndrome. Am J Hum Genet 92:259-264, 2013

Yamanaka, S. & Blau H.M. (2010) Nuclear reprogramming to a pluripotent state by three approaches. Nature 2010, 465, 704-712.



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