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MRC DiMeN Doctoral Training Partnership: Pneumonia in-a-dish: developing a novel iPSC-derived human alveolar model to assess polycation signalling in the inflamed lung of critically ill patients


   MRC DiMeN Doctoral Training Partnership

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  Dr Polina Yarova, Prof John Simpson  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

This MRC DiMeN funded iCASE project provides an exciting opportunity for a motivated and scientifically driven Student to engage with an interdisciplinary team of academics, clinicians and an industrial partner aiming to help tackling one of the most devastating pro-inflammatory lung diseases such as pneumonia. Pneumonia is responsible for ~25% mortality from lung disease in the UK and ~22% of overall deaths of children under six worldwide. Pneumonia is especially prevalent within intensive care units, affecting between 11% to 28% of critically ill patients with a mortality rate of up to 50%. Antibiotics overuse causes uprise of antimicrobial resistance, thus new approaches that could help to improve lung defence and immune function are urgently needed.

This project would provide key insights into the pathophysiological roles of the cation/calcium-sensing receptor (CaSR) during pneumonia and test efficacy of clinical-grade CaSR modulators in promoting lung defence using novel lung disease modelling approaches.

With help and guidance from our inter-disciplinary team and collaboration network, the successful Candidate will develop a novel 3D “pneumonia in a dish” alveolar model using human induced pluripotent stem cells (hiPSCs) to (i) understand the functional interplay between lung immunity and polycation signalling in critical illness, (ii) manipulate the system genetically and pharmacologically to gain insight of the disease mechanisms and potential therapeutic interventions in the area of unmet clinical need, pneumonia.

HiPSCs-derived 3D lung models provide unique platforms for genotype-tailored research, measuring effectiveness of specific treatments; moreover, patient-specific stem cell-derived lung models are an important step towards developing regenerative and precision medicines of the future. The work will also involve gene editing tools such as CRISPR/Cas9 to silence the genes of interest, and use a variety of pharmacological, biochemical and biophysical techniques to elucidate polycation signalling in the inflamed lung.

Our team will provide Student with training in the following skills areas:

-         Interdisciplinary skills, spanning from in vitro pharmacology, cell signalling, biophysics, biochemistry, imaging, stem cell biology, 3D cell culture, analysis of clinical samples, pre-clinical and translational research.

-         Quantitative skills, including computational data analysis, 3D reconstruction of confocal images, statistics, data management.

-         Modelling of complex biological systems with focus on the human lung in a healthy and pathological setting.

The successful Candidate will be based in Newcastle University, School of Medicine. They will also receive gene editing training in Cardiff University as part of our collaboration with Dr Branko Latinkic and Wales Gene Park. There will be numerous opportunities to present their work at national and international conferences during their study. Finally, the Student will also gain an invaluable industrial experience with our iCASE partner STEMCELL, Cambridge, during the placement at the end of their study.

Please contact [Email Address Removed] for more information.

Details of the supervisory tam can be found here:

https://www.researchgate.net/profile/Polina-Yarova

https://www.ncl.ac.uk/medical-sciences/people/profile/polinayarova.html

https://www.ncl.ac.uk/medical-sciences/people/profile/jsimpson.html

https://www.ncl.ac.uk/medical-sciences/people/profile/vsevolodtelezhkin.html

https://www.stemcell.com/

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/how-to-apply


Funding Notes

Fully funded by the MRC for 4yrs, including a minimum of 3 months working with an industry partner.

Funding will cover tuition fees and an enhanced stipend (around £20,168). We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: https://www.dimen.org.uk/eligibility-criteria
Studentships commence: 1st October 2023
Good luck!

References

Primary supervisor, Dr Polina Yarova (expert in lung modelling, CaSR signalling and inflammation):
1. Yarova PL, Huang P, Schepelmann MW, Bruce R, Ecker R, Nica R, Telezhkin V, Traini D, Dos Reis LG, Kidd EJ, Ford WR, Broadley KJ, Kariuki BM, Corrigan CJ, Ward JPT, Kemp PJ, Riccardi D. Characterization of Negative Allosteric Modulators of the Calcium-Sensing Receptor for Repurposing as a Treatment of Asthma. Journal of Pharmacology and Experimental Therapeutics 2021; 376: 51-63.
2. Schepelmann M, Yarova PL, Lopez-Fernandez I, Davies TS, Brennan SC, Edwards PJ, Aggarwal A, Graca J, Rietdorf K, Matchkov V, Fenton RA, Chang W, Krssak M, Stewart A, Broadley KJ, Ward DT, Price SA, Edwards DH, Kemp PJ, Riccardi D. The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure. Am J Physiol-Cell Ph 2016; 310: C193-C204.
3. Yarova PL, Stewart AL, Sathish V, Britt RD, Thompson MA, Lowe APP, Freeman M, Aravamudan B, Kita H, Brennan SC, Schepelmann M, Davies T, Yung S, Cholisoh Z, Kidd EJ, Ford WR, Broadley KJ, Rietdorf K, Chang WH, Bin Khayat ME, Ward DT, Corrigan CJ, Ward JPT, Kemp PJ, Pabelick CM, Prakash YS, Riccardi D. Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Sci Transl Med 2015; 7.
4. Yarova PL, Lowe APP, Brennan SK, Rietdorf K, Cholisoh Z, Chang W, Kidd EJ, Ford W, Corrigan CJ, Ward JPT, Kemp PJ, Riccardi D. A Novel Therapeutic For Treating Inflammatory Lung Disorders. Am J Resp Crit Care 2014; 189.
Secondary supervisor, Professor John Simpson (clinician with vast expertise in critical illness pro-inflammatory lung disease and immunity):
1. Scott J, Ruchaud-Sparagano MH, Musgrave K, Roy AI, Wright SE, Perry JD, Conway Morris A, Rostron AJ, Simpson AJ. Phosphoinositide 3-Kinase delta Inhibition Improves Neutrophil Bacterial Killing in Critically Ill Patients at High Risk of Infection. J Immunol 2021; 207: 1776-1784.
2. Wood AJ, Vassallo AM, Ruchaud-Sparagano MH, Scott J, Zinnato C, Gonzalez-Tejedo C, Kishore K, D'Santos CS, Simpson AJ, Menon DK, Summers C, Chilvers ER, Okkenhaug K, Morris AC. C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodeling. JCI Insight 2020; 5.
3. Hellyer TP, McAuley DF, Walsh TS, Anderson N, Conway Morris A, Singh S, Dark P, Roy AI, Perkins GD, McMullan R, Emerson LM, Blackwood B, Wright SE, Kefala K, O'Kane CM, Baudouin SV, Paterson RL, Rostron AJ, Agus A, Bannard-Smith J, Robin NM, Welters ID, Bassford C, Yates B, Spencer C, Laha SK, Hulme J, Bonner S, Linnett V, Sonksen J, Van Den Broeck T, Boschman G, Keenan DJ, Scott J, Allen AJ, Phair G, Parker J, Bowett SA, Simpson AJ. Biomarker-guided antibiotic stewardship in suspected ventilator-associated pneumonia (VAPrapid2): a randomised controlled trial and process evaluation. Lancet Respir Med 2020; 8: 182-191.
Tertiary supervisor, Dr Vsevolod Telezhkin (expert in hiPSCs, biophysics and chronic pain modelling):
1. Telezhkin V, Straccia M, Yarova P, Pardo M, Yung S, Vinh NN, Hancock JM, Barriga GGD, Brown DA, Rosser AE, Brown JT, Canals JM, Randall AD, Allen ND, Kemp PJ. Kv7 channels are upregulated during striatal neuron development and promote maturation of human iPSC-derived neurons. Pflug Arch Eur J Phy 2018; 470: 1359-1376.
2. Telezhkin V, Schnell C, Yarova P, Yung S, Cope E, Hughes A, Thompson BA, Sanders P, Geater C, Hancock JM, Joy S, Badder L, Connor-Robson N, Comella A, Straccia M, Bombau G, Brown JT, Canals JM, Randall AD, Allen ND, Kemp PJ. Forced cell cycle exit and modulation of GABA(A), CREB, and GSK3 beta signaling promote functional maturation of induced pluripotent stem cell-derived neurons. Am J Physiol-Cell Ph 2016; 310: C520-C541.
3. Kemp PJ, Rushton DJ, Yarova PL, Schnell C, Geater C, Hancock JM, Wieland A, Hughes A, Badder L, Cope E, Riccardi D, Randall AD, Brown JT, Allen ND, Telezhkin V. Improving and accelerating the differentiation and functional maturation of human stem cell-derived neurons: role of extracellular calcium and GABA. J Physiol-London 2016; 594: 6583-6594.
iCASE partner, STEMCELL Technologies Inc. (a world leader in developing, manufacture and distribution of life science research tools specialising in stem cells research products):
1. Hawkins F, Kramer P, Jacob A, Driver I, Thomas DC, McCauley KB, Skvir N, Crane AM, Kurmann AA, Hollenberg AN, Nguyen S, Wong BG, Khalil AS, Huang SX, Guttentag S, Rock JR, Shannon JM, Davis BR, Kotton DN. Prospective isolation of NKX2-1-expressing human lung progenitors derived from pluripotent stem cells. J Clin Invest 2017; 127: 2277-2294.
2. Meseguer-Ripolles J, Wang Y, Sorteberg A, Sharma A, Ding NL, Lucendo-Villarin B, Kramer P, Segeritz CP, Hay DC. Hepatic Progenitor Specification from Pluripotent Stem Cells using a Defined Differentiation System. J Vis Exp 2020.
General references:
1. Lasbury ME, Merali S, Durant PJ, Tschang D, Ray CA, Lee CH. Polyamine-mediated apoptosis of alveolar macrophages during Pneumocystis pneumonia. J Biol Chem 2007, 282(15): 11009-11020.
2. Jain V, Raina S, Gheware AP, Singh R, Rehman R, Negi V, et al. Reduction in polyamine catabolism leads to spermine-mediated airway epithelial injury and induces asthma features. Allergy 2018, 73(10): 2033-2045.
3. Saumon G, Soler P, Martet G. Effect of polycations on barrier and transport properties of alveolar epithelium in situ. Am J Physiol 1995, 269(2 Pt 1): L185-194.
4. Lopez-Fernandez I, Schepelmann M, Brennan SC, Yarova PL, Riccardi D. The calcium-sensing receptor: one of a kind. Exp Physiol 2015, 100(12): 1392-1399.
5. Klein GL, Castro SM, Garofalo RP. The calcium-sensing receptor as a mediator of inflammation. Semin Cell Dev Biol 2016, 49: 52-56.
6. Hendy GN, Canaff L. Calcium-Sensing Receptor Gene: Regulation of Expression. Front Physiol 2016, 7: 394.
7. Zeng X, Zhu L, Xiao R, Liu B, Sun M, Liu F, et al. Hypoxia-Induced Mitogenic Factor Acts as a Nonclassical Ligand of Calcium-Sensing Receptor, Therapeutically Exploitable for Intermittent Hypoxia-Induced Pulmonary Hypertension. Hypertension 2017, 69(5): 844-854.
8. Nawroth JC, Barrile R, Conegliano D, van Riet S, Hiemstra PS, Villenave R. Stem cell-based Lung-on-Chips: The best of both worlds? Adv Drug Deliv Rev 2019, 140: 12-32.
9. Bluhmki T, Traub S, Muller AK, Bitzer S, Schruf E, Bammert MT, et al. Functional human iPSC-derived alveolar-like cells cultured in a miniaturized 96Transwell air-liquid interface model. Sci Rep 2021, 11(1): 17028.
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