Projects for September 2021 Entry
Partner: Merck, Sharp & Dohme
Research Area: Advanced Therapeutics
Project Description: The ability to learn and remember is essential for survival of all animal species. Fundamental questions remain about how memories are encoded and stored in the brain. The formation of long-term memories, also referred to as memory consolidation, requires new gene transcription and protein synthesis. As long-term memory is established or modified through gene expression changes, epigenetic mechanisms that regulate gene transcription are likely to have key roles in memory consolidation. Furthermore, deficits in memory consolidation are thought to be the primary cause of age-related learning deficits. Thus, manipulating the epigenome may help prevent or even treat memory deficits in old age. Indeed, histone deacetylases have been successfully targeted to enhance learning in aged mice as well as various models of neurodegenerative diseases like Alzheimer’s disease. Our recent preliminary analysis of mice with loss of KDM5B histone demethylase activity suggest a similar role for these enzymes, and therefore that targeting these enzymes might provide a novel way to treat age-related memory deficits.
The aim of this project will be to determine to what extent specific types of histone methylation is associated with learning deficits associated with old age, if deletion or inhibition of KDM5B histone demethylase activity can restore these learning deficits and to screen for and develop more potent/specific KDM5B for therapy.
Publications: Suetterlin, P., Hurley, S., Mohan, C., Riegman, K.L.H., Pagani, M., Caruso, A., Ellegood, J., Galbusera, A., Crespo-Enriquez, I., Michetti, C., Yee, Y., Ellingford, R., Brock, O., Delogu, A., Francis-West, P., Lerch, J.P., Scattoni, M.L., Fernandes, C. & Basson, M.A. (2018). Altered neocortical gene expression, brain overgrowth and functional over-connectivity in Chd8 haploinsufficient mice. Cereb. Cortex. 28:2192-2206.
Vigil FA, Mizuno K, Lucchesi W, Comamala VV, Giese KP (2017). Prevention of long-term memory loss after retrieval by an endogenous CaMKII inhibitor. Sci Rep 7, 4040.
Research Area: Accelerating (Precision) Medicines & Diagnostics Discovery and Translation
Project Description: Ankylosing spondylitis (AS) is a common chronic immune-mediated inflammatory disease that affects primarily the spine and pelvis. It is highly heritable, and is thought to be driven by interaction between the host immune-system and a common environmental driver, likely gut bacteriae. Diagnosis of AS is challenging, particularly early in the disease course. There are limited biomarkers to assess disease activity or predict radiographic progression. The project will use large case-control serum collections held by Professor Brown to investigate proteomic biomarkers of disease diagnosis, activity, and radiographic severity and progression. Association of proteins with known genetic variants associated with AS will be investigated. Multiomic analysis including proteomic data, as well as transcriptomic and methylation data (already held by Professor Brown), will also be performed. Biomarker performance to identify early cases of AS will be assessed using prospective studies currently being undertaken in North America. Where novel biomarkers are identified, further studies will be performed to investigate their source, and relationship to disease pathogenesis. The nature of these studies will be determined by the properties of the biomarkers involved.
The student involved in the project will develop skills in proteomics methodology, analysis methods including multiomic and genomic/pQTL analysis, and other molecular/cell biology methodology such as flow cytometry to follow-up the proteomic findings.
Year by year objectives would include:
Year 1 – Completion of proteomic measurements and case-control and case clinical manifestation analysis.
Year 2 – Combination analysis of proteomic findings with genomic, transcriptomic and epigenetic data.
Year 3 – Replication studies of proteomic markers using early AS case and chronic back pain cohorts. Cell and molecular biology investigation of identified protein biomarkers.
Year 4 – Complete functional studies, write-up.
Publications: ‘Genetic variants in ERAP1 and ERAP2 associated with immune-mediated diseases influence protein expression and isoform profile’. Hanson A, Cuddihy T, Haynes K, Loo D, Morton CJ, Opperman U, Leo P, Thomas GP, Le Cao KA, Kenna TJ, Brown MA. Arthritis Rheum, 70(2):255-265, 2018.
Perucha E, Melchiotti R, Bibby J, Wu W, Stensgaard Frederiksen, Roberts CA, Hall Z, LeFriec G, Robertson KA, Gammeltoft Gerwien J, Taams LS, Griffin JL, de Rinaldis E, van Baarsen LGM, Kemper K, Ghazal P, Cope AP. The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 effector T cells. Nat Comms 10:498, 2019.
Research Area: Advanced Therapeutics
Project Description: 5-10% of women experience a moderate to severe depressive episode in pregnancy, which left untreated can cause serious problems for the woman & her baby.
NICE (2014) guidelines for treating prenatal depression recommends women be offered psychological therapy &/or antidepressant medication. However, therapy only works for about 40% of depressed people & can take several months to be effective. Also, it is unclear if antidepressants are safe in pregnancy. Consequently, many women refuse, or stop taking, antidepressants prenatally, which is concerning because up to 70% of them will be depressed again by the time they give birth.
Repetitive Transcranial Magnetic Stimulation (rTMS) is a scientifically proven, ‘non-drug’, therapy which uses a focused magnetic current to stimulate or inhibit brain activity in areas that are, respectively, under– or over- active in depression. It is at least as effective as antidepressants, & NICE (2015) state that rTMS ‘works well enough for use in the NHS’ & ‘shows no major safety concerns’. A recent study supports the use of rTMS to treat depression during pregnancy, but it was small & not conducted in the UK. The current study aims to:
a) Compare the effectiveness oftworTMS protocols in pregnant women with moderate–to–severe depression.
b) Use a technique called electroencephalography to measure brain wave patterns in women before & during treatment to better understandi)how rTMS works & ii) which women are most likely to respond. (This simply requires women to wear a rubber cap for 5 minutes before three rTMS sessions).
Publications: Craig M.C., Sethna V, Gudbrandsen M, Pariente CM, SeneviratneT, Stoencheva V, Sethi A, Catani M, Brammer M, Murphy DGM, & Daley E. Birth of the Blues – Emotional Sound Processing in Infants Exposed to Prenatal Maternal Depression. Psychological Medicine (In Press).
Mutz J, Vipulananthan V, Carter B, Hurlemann R, Fu CHY, Young AH. Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis. BMJ. 2019; 364: 1079. doi:10.1136/bmj.l1079
Research Area: Advanced Therapeutics, Accelerating (Precision) Medicines & Diagnostics Discovery and Translation
Project Description: The United Kingdom adult population prevalence of obesity is 30% and with 30% of children – overweight or obese. Additionally, 26% of women of reproductive age are obese and one in five pregnant women is obese. We have recently shown, that the offspring of obese mothers have increased appetite, body weights, fat mass and markers of obesity-induced liver disease (non-alcoholic fatty liver disease, NAFLD) compared with offspring of lean mothers. Our results have been confirmed in humans such that the children of obese mothers show increased obesity and NAFLD. NAFLD is predicted to become the commonest cause of liver cirrhosis/failure and transplantation within the next decade or less. The precise mechanism by which this trans-generational transmission of obesity and NAFLD occur remains unclear.
Obesity and NAFLD are known to develop at least partially in response to gut bacteria. Commensal bacteria are transferred between co-housed animals and can cause the transmission of both obesity and NAFLD traits. Therefore, it is likely that the transmission of obesity from mother to offspring during the peri-natal and post-natal periods is at least partially via the transmission of maternal commensal micro-organisms to the new born. This has recently been strongly supported through the use of germ-free mice and their colonisation with stools from the offspring of obese human subjects. We now seek to study this further using agents that target the pathways through which the gut microbiota act.
Publications: Mouralidarane A, Soeda J, Visconti-Pugmire C, Samuelsson A-M, Pombo J, Maragkoudaki X, Butt A, Saraswati R, Novelli M, Fusai G, Poston L, Taylor PD & Oben JA. (2013). Maternal Obesity Programs Offspring Non-Alcoholic Fatty Liver Disease via Innate Immune Dysfunction in Mice. Hepatology 58, 128-138.
Oben JA, Mouralidarane A, Samuelsson AM, Matthews, PA, Morgan ML, McKee C, Soeda J, Fernandez-Twinn DS, Martin-Gronert MS, Ozanne SE, Sigala B, Novelli, M Poston L and Taylor PD. (2010). Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice. J Hepatology. 52(6): p. 913-20. (plus Editorial Comment).
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.
When choosing an iCASE project from those available for September 2021 Entry, in the funding section of the online application from please enter the funding code ‘MRCDTP2021_’ followed by the project number that corresponds to your chosen project e.g:
Deadline for applications: Sunday 29th November, 23:59pm
Interviews: Wednesday 27th & Thursday 28th January – iCASE studentships will commence in September 2021. For further information please visit our application support page or contact firstname.lastname@example.org.