Projects for September 2022 Entry
Partner: STEMCELL Technologies UK Ltd
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.
Partner: Sosei-Heptares Therapeutics Ltd.
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.
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.
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:
- Profile the physicochemical properties of mucus that are important for particle deposition, penetration and interactions,
- 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,
- 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.
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.
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).
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.