iCASE Projects

Projects for September 2022 Entry

Co-Supervisors:

Partner: STEMCELL Technologies UK Ltd

Theme: CM-HD

Project Description: Our current understanding of the initial stages of many cancers is still limited. This is because current human cancer models are often based on immortalised cell lines and cells derived from late-stage tumours. While these studies are important for assessing mature tumour behaviour, they are less helpful for deciphering critical steps during tumour formation and metastasis. Because of this gap in our knowledge, it is difficult to pinpoint the causative events, which may be of potential clinical value as early markers. Here, we use human induced pluripotent stem cells to model cancer initiation and migration. We are specifically interested in neuroblastoma, a rare paediatric cancer, which arises from embryonic cells called neural crest cells. These cells are multipotent stem cells that give rise to diverse tissues such as melanocytes, Schwann cells, craniofacial skeleton and peripheral nervous system. During embryogenesis, neural crest cells delaminate from the neural tube, undergo epithelial-mesenchymal transition and migrate long distances in a process akin to metastasis. Our ultimate aim is to establish an assay allowing us to use patient-derived hiPSCs to assess the differentiation capacity of normal and diseased hiPSCs. To achieve this, we need to define reproducible protocols for differentiation of hiPSCs to neural crest. We will profile the developmental transitions as they differentiate to neural crest lineages including sympathetic nervous system and Schwann cells, which will allow us to pinpoint pathological triggers during differentiation.

Publications: Gonzalez Malagon SG, Lopez Munoz AM, Doro D, Bolger T, Poon E, Tucker E, Adel Al-Lami H, Krause M, Phiel C, Chesler L and Liu KJ.GSK3 controls migration of the neural crest lineage. Nature Communications,9, 116 2018. doi:10.1038/s41467-018-03512-5

Russell JP, Lim X, Santambrogio A, Yianni V, Kemkem Y, Wang B, Fish M, Haston S, Grabek A, Hallang S, Lodge EJ, Patist AL, Schedl A, Mollard P, Nusse R, Andoniadou CL. Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells. Elife. (2021) Jan 5;10:e59142. doi: 10.7554/eLife.59142.

Co-Supervisors:

Partner: Helperby Therapeutics Groups Ltd

Theme: CM-HD

Project Description: Antimicrobial resistance (AMR) to gram-negative pathogens responsible for the majority of nosocomial infections such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii represents a significant challenge to future healthcare provision. This situation has been further negatively exacerbated by a shortage of new antibiotics in the pharmaceutical pipeline or in early-stage clinical trials. A combination of the high cost of drug development and a short window of use for financial return in the development of new antibiotics combined with the continued increase in prevalence of AMR has further reduced the armoury of antibiotic therapies available to us, rendering some clinical conditions virtually untreatable, thereby leading to a concomitant decrease in both quality of life and increased mortality of patients suffering from such infections. The development of novel strategies for the treatment of infections caused by multidrug resistant (MDR) gram-negative pathogens therefore represents an urgent unmet clinical need. One novel approach involves the use of so called ‘antibiotic enhancers’ that when used at low doses enhance the antibacterial activity of conventional antibiotics against MDR pathogens. One such compound is the small quinolone-derived compound HT61. HT61 has previously been demonstrated to exhibit bactericidal activity against gram-positive bacteria including methicillin susceptible Staphylococcus aureus(MSSA) and methicillin resistant S.aureus (MRSA). When combined with classical antibiotics such as neomycin, gentamicin and mupirocin, HT61 enhanced their bactericidal activity in vitro. In a second study, whilst HT61 failed to demonstrate bactericidal activity against a small selection of both sensitive and MDR strains of the gram-negative bacteria P.aeruginosain vitro or in vivo when used as a monotherapy, in vitro and in vivo studies revealed significant synergism in the antimicrobial activity of tobramycin when used in combination. This studentship will further investigate the synergistic interactions of HT61 alongside tobramycin against a broad panel of disease relevant clinical isolates of P.aeruginosa, whilst also performing proof-of-concept studies to extend this synergism with HT61 against other ESKAPE gram-negative pathogens including K.pneumoniaeand A.baumannii demonstrating both sensitivity and resistance toantibiotics such as tobramycin and alternative antibiotics such as meropenem and ampicillin-sulbactam.

Publications: Hu Y, Coates AR. Enhancement by novel anti-methicillin-resistant Staphylococcus aureus compound HT61 of the activity of neomycin, gentamicin, mupirocin and chlorhexidine: in vitro and in vivo studies. J Antimicrob Chemother. 2013 Feb;68(2):374-84. doi: 10.1093/jac/dks384. Epub 2012 Oct 4. PMID: 23042813.

Amison RT, Faure ME, O’Shaughnessy BG, Bruce KD, Hu Y, Coates A, Page CP. The small quinolone derived compound HT61 enhances the effect of tobramycin against Pseudomonas aeruginosa in vitro and in vivo. Pulm Pharmacol Ther. 2020 Apr;61:101884. doi: 10.1016/j.pupt.2019.101884. Epub 2019 Dec 27. PMID: 31887372.

Manzo G, Hind CK, Ferguson PM, Amison RT, Hodgson-Casson AC, Ciazynska KA, Weller BJ, Clarke M, Lam C, Man RCH, Shaughnessy BGO, Clifford M, Bui TT, Drake AF, Atkinson RA, Lam JKW, Pitchford SC, Page CP, Phoenix DA, Lorenz CD, Sutton JM, Mason AJ. A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy. Commun Biol. 2020 Nov 27;3(1):697. doi: 10.1038/s42003-020-01420-3. PMID: 33247193; PMCID: PMC7699649.

Co-Supervisors:

Partner: Paxman Coolers Ltd.

Theme: BE-MI

Project Description: This project will use new technologies with the aim of developing effective and acceptable interventions for children and young people to reduce the adverse health consequences of obesity, e.g. diabetes, high blood cholesterol and non-alcoholic fatty liver disease.  

Year 1: The student will learn device design with the industrial partner (Paxman Coolers Ltd).  A cooling garment will be designed to deliver intermittent cold exposure (ICE) for 4 weeks to obese and lean children/young people of both sexes. The student will measure physiological responses and will learn to use advanced imaging to study the impact on metabolic tissues (liver, muscle and brown or white adipose tissue (BAT/WAT)) and will evaluate the gut microbes and whether they produce products that can influence risk of obesity.  

Year 2: Detailed analysis of imaging data, and high-throughput molecular analysis techniques will be used to study metabolic pathway changes in adipose tissue samples, and changes in glucose, cholesterol and similar substances in blood.  

Year 3: The student will evaluate whether cold exposure causes a shift from ‘obesity-associated’ to ‘lean’ microbes, and will learn to integrate complex analysis techniques. The impact of age and sex on responses to cold exposure will be studied. If particular groups of children are likely to be more/less responsive, modified ICE protocols or combined treatments to enhance protection from metabolic consequences of obesity will be studied in proof-of-concept studies of children with obesity-associated fatty liver disease. 

Year 4: Support in final analysis, writing and presentation of results to scientific audiences. 

Publications: Ovadia C, Perdones-Montero C, Spagou K, Smith A, Sarafian MH, Romero MG, Bellafante E, Clarke LD, Sadiq F, Nikolova V, Mitchell A, Dixon PH, Santa-Pinter N, Wahlström A, Abu-Hayyeh S, Walters J, Marschall HU, Holmes E, Marchesi JR, Williamson C. Enhanced microbial bile acid deconjugation and impaired ileal uptake in pregnancy repress intestinal regulation of bile acid synthesis. Hepatology. 2019; 70(1):276-293. doi: 10.1002/hep.30661. PMID: 30983011 

Defining paediatric metabolic (dysfunction)-associated fatty liver disease: an international expert consensus statement. Eslam M, Alkhouri N, Vajro P, Baumann U, Weiss R, Socha P, Marcus C, Lee WS, Kelly D, Porta G, El-Guindi MA, Alisi A, Mann JP, Mouane N, Baur LA, Dhawan A, George J. Lancet Gastroenterol Hepatol. 2021 Aug 5:S2468-1253(21)00183-7. doi: 10.1016/S2468-1253(21)00183-7. 

Co-Supervisors:

Partner: Sosei-Heptares Therapeutics Ltd.

Theme: CM-HD

Project Description: This research utilises knowledge gained over 5 years collaborating with Heptares, plus BBSRC funding (to Cox, 2016-2021) that has established how nutrient-sensitive receptors modulate gut functions via gut hormones that make us feel full. We now aim to elucidate how certain receptor pathways may influence acute colitis in a mouse model of inflammatory bowel disease (IBD). New Heptares drugs that are selective for these receptor-pathways will be tested to see if they protect against or reduce colitis in mice. Co-supervisor O’Byrne brings complementary expertise in stress effects on rodent brain function, which will be important for our proposed animal studies where the gut-brain axis is involved. Training in tissue and animal techniques will identify which gut cell-types mediate signal changes in a mouse colitis model that resembles human colitis. Year 2 work will establish the potency of new GPCR anti-inflammatory drugs in vitro and in vivo (after passing HO modules 1-4). In years 2-3,mice will receive optimal drug treatment(s)followed by gut function tests, histological and biomarker assessments for colitis, the latter undertaken by the student at Heptares and Fidelta (a CRO in Zagreb, who provide pathology support to Heptares). These planned placements will provide interactions with UK-and EU-based scientists. Notably this is a multi-disciplinary grouping that includes biomedical, clinical and bio-engineer scientists based in KCL, Heptares, Imperial and Fidelta. Student placements will also provide exposure to the highest scientific standards of academic-commercial collaborations and we will publish our findings in high impact scientific journals. Twice monthly meetings with all collaborators, and separate smaller twice monthly meetings between the Cox lab and Heptares will continue. The student will contribute to both fora ,sharing their data and contributing to discussions on the direction of research. This will allow the student to refine their communication skills and adopt best scientific practice.

Publications: Cox (KCL): Bidirectional GPR119 Agonism Requires Peptide YY and Glucose for Activity in Mouse and Human Colon Mucosa.Tough IR, Forbes S, Herzog H, Jones RM, Schwartz TW, Cox HM. (2018) Endocrinology, 159(4):1704-1717. doi: 10.1210/en.2017-03172.

O’Byrne (KCL): Ivanova D, Li XF, McIntyre C, Liu Y, Kong L, O’Byrne KT. (2021) Endocrinology, 162(12): bqab206. doi: 10.1210/endocr/bqab206.

Brown (Heptares): From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer’s disease. Brown AJ, et al. (2021) Cell, 184(24): 5886-5901.e22. doi: 10.1016/j.cell.2021.11.001.

Suzuki (Heptares): Gastrointestinal and metabolic function in the MPTP-treated macaque model of Parkinson’s disease. Delamarre A, MacSweeney C, Suzuki R, Brown AJ, Li Q, Pioli EY, Bezard E. (2020) Heliyon, 6(12):e05771. doi: 10.1016/j.heliyon.2020.e05771.

Co-Supervisors:

Partner: GSK Consumer Healthcare

Theme: BE-MI

Project Description: This application follows our nearly completed study on the efficacy of intra oral scanners used to measure tooth wear accurately. We have shown that the limits of handheld intra oral scanners are 40 um on polished enamel, 80 um on natural free form surfaces and in the mouth greater than 130 um across the arch, and published our work. The next phase of our work is to expand this area and test the hypothesis on existing scans from orthodontic libraries of study casts which have been scanned and stored. This will build on our work, fit with on-going PhDs interrogating the accuracy of software (iCase BBSRC, China PhD scholarship and Saudi funded students) to eliminate the need for reference areas on natural freeform surfaces of teeth. The eventual aim fits with the UK pharmaceutical industry need to clinically verify the action of oral care products on prevention of erosion. Sales of toothbrush and toothpaste were over a billion in 2020. Previous funding from oral care industry has allowed our group to clarify the risk factors and understand which risk groups have progression. Severe tooth wear often wears over 50% of a tooth in 10-20 years so our finding that intra oral scanner can measure over 130 um is within the tolerance. The innovation of this PhD is to interrogate surface matching technology to the next level. This PhD will train high-precision imaging and measurement, chemical analysis, software development and foster expertise for a career in industry or academia.

Publications:

Superimposition of sequential scans to measure erosion on unpolished and curved human enamel Mylonas, P., Moazzez, R. & Bartlett, D., 29 Oct 2021, (Accepted/In press) In: Journal of Dentistry.

The measurement threshold and limitations of an intra-oral scanner on polished human enamel Charalambous, P., O’Toole, S., Bull, T., Bartlett, D. & Austin, R., Apr 2021, In: Dental Materials : official publication of the Academy of Dental Materials. 37, 4, p. 648-654.

Please note: This project (MRCDTP_2022iCASE6) will not be funded by the Medical Research Council (MRC). This studentship will be co-funded by King’s College London (KCL) and the Industry Partner. Visit FAQ’s for further information.

Co-Supervisors:

Partner: Nanopharm Ltd, an Aptar Pharma Company

Theme: CM-HD

Project Description: The deposition of particles in the nose is important in the transmission of infectious disease and the delivery of nasally administered therapies.  This project will study the interactions between nasally inhaled particles and the mucus lining of the nasal cavity.  The aim is to characterise the biophysics of nasal mucus, from the nano-to macro-scale, and develop a biorelevant mucus simulant as an easy-to-handle, reproducible research tool to study physical and chemical interactions with pharmaceutical particles. The project will work across the boundaries of biology, formulation chemistry, materials science and machine learning/computational statistics to develop new tools to guide the design of novel nasally administered therapies (including mucus-modifying formulations) and has potential applications in the study of disease transmission. 

The project will have three phases: 

  1. Profile the physicochemical properties of mucus that are important for particle deposition, penetration and interactions, 
  2. Develop a mucus simulant for in vitro testing to study post-deposition ‘partico-kinetics’ and apply these data in mechanistic computational models to predict drug bioavailability, 
  3. Apply the in vitro tools to test marketed products and muco-interactive candidates for the development of novel formulations for small and large therapeutic molecules. 

Skills/training: As well as inter-sector and inter-disciplinary experience, the project will provide in-depth technical training in material characterisation techniques, including shear- and micro-rheology (particle-tracking), diffusion NMR, small-angle neutron scattering, light scattering and confocal microscopy.  Other research skills include organotypic cell culture, nasal liquid formulation, nasal powder formulation, design of experiments methodology, statistical modelling, machine learning techniques. 

Publications:

Wingrove J, . Forbes B.  Characterisation of nasal devices for delivery of insulin to the brain and evaluation in humans using functional magnetic resonance imaging.  Journal of Controlled Release 302: 140-147 (2019) 

Da Silva …… Dreiss C. Thermoresponsive Triblock-copolymers of polyethylene oxide and polymethacrylates: linking chemistry, nanoscale morphology, and rheological properties, Advanced Functional Materials, 2021, 2109010.

Zapata del Bano…Rossi I. Development of a nasal spray containing a novel human recombinant antibody for SARS-CoV-2 therapy. Drug Delivery to the Lungs, Volume 32, 2021.  

Ganley W J ….. Price, R. Simulation Informed Design and Performance of In Vitro Bioequivalence Trials for Particle Size Distributions, AAPSJ 22, 139 (2020) 

Please note: This project (MRCDTP_2022iCASE7) will not be funded by the Medical Research Council (MRC). This studentship will be co-funded by King’s College London (KCL) and the Industry Partner. Visit FAQ’s for further information.

Co-Supervisors:

Partner: Grünenthal

Theme: NS-MH

Project Description: Diabetes is one of the major health challenges of our time, affecting about 10% of the global population. Complications of longstanding disease affect many organ systems and are regularly serious. Diabetic neuropathy (DN) is one of the leading causes of chronic neuropathic pain, but current therapies leave patients without satisfactory pain relief. About half of all patients with diabetes develop diabetic sensory neuropathy, and many of these suffer from chronic debilitating pain that is difficult to treat. Despite that DN is an important cause of pain, its most characteristic symptom is sensory loss, which in itself contributes to foot ulcers and amputations. Like other types of neuropathy, DN is characterized by a loss of innervation of the skin (an anatomical loss of nerve fibres), but its relationship to pain and sensory loss is unclear. The oxidative and metabolic stress typical of diabetes leads to production of multiple reactive metabolites, which all stimulate the ion channel TRPA1. TRPA1 is expressed in a large subset of pain sensing (nociceptive) sensory neurons and has been hotly pursued as a target for novel analgesic drugs. The supervisors have discovered that diabetic mice lacking TRPA1 are protected from the anatomical signs of neuropathy (no loss of skin innervation), and these observations suggest that TRPA1 may contribute to the onset of DN, as well as producing pain. During this project, the mechanisms responsible for DN and sensory abnormalities will be examined in isolated primary sensory neurons, and in sensory neurons derived from human induced pluripotent stem cells (hIPSCs).

Publications:

Goebel, A, Krock, E, Gentry, C, Israel, MR, Jurczak, A, Morado Urbina, C, Sandor, K, Vastani, N, Maurer, M, Cuhadar, U, Sensi, S, Nomura, Y, Menezes, J, Baharpoor, A, Brieskorn, L, Sandström, A, Tour, J, Kadetoff, D, Haglund, L, Kosek, E, Bevan, S, Svensson, CI & Andersson, DA 2021, ‘Passive transfer of fibromyalgia symptoms from patients to mice’, The Journal of clinical investigation, vol. 131, no. 13, e144201. Read Here

Quallo, T, Vastani, N, Horridge, E, Gentry, C, Parra, A, Moss, S, Viana, F, Belmonte, C, Andersson, DA & Bevan, S 2015, ‘TRPM8 is a neuronal osmosensor that regulates eye blinking in mice’, Nature Communications, vol. 6, no. 1, 7150, pp. 1-12.  Read Here

Simeoli, R., Montague, K., Jones, H. R., Castaldi, L., Chambers, D., Kelleher, J. H., Vacca, V., Pitcher, T., Grist, J., Al-Ahdal, H., Wong, L-F., Perretti, M., Lai, J., Mouritzen, P., Heppenstall, P. & Malcangio, M., Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma24 Nov 2017, Nature Communications. 8, 1, p. 1778

All iCASE projects are available as a straight 4 year PhD. Applicants may apply for one project only. You may contact project supervisors for further information about project opportunities. This does not commit a candidate to these laboratories.