- Total grants
- Total funders
- Total recipients
- Earliest award date
- 01 Apr 2016
- Latest award date
- 31 May 2016
- Total GBP grants
- Total GBP awarded
- Largest GBP award
- Smallest GBP award
- Total Non-GBP grants
This application requests funds for two speakers from Zimbabwe to attend a conference I am co-organising at St Antony's College, Oxford. The theme is Health and Politics in Zimbabwe and the Diasporas. The Research Day will examine the politics of health provision, health culture, change and development, exploring history, practice and impacts. The experiences of Zimbabwean health professionals abroad will be a key part of the conversation. The day will include a mix of well-known and up and coming researchers and practitioners, academics and non-academics. It will be a forum for debate, shared experiences, new research and future thinking. My invited speakers are contacts working in Zimbabwe on 1) health policy and 2) epilepsy. I have conducted a 2 week pilot visit to Zimbabwe in order to identify field sites for a larger grant application on the history of epilepsy in Africa. Both of these contacts will be instrumental for future research. In addition to the Oxford conference, I will organise meetings for the speakers with researchers interested in mental health and epilepsy in Zimbabwe/Africa, as well as visits to the Wellcome Unit for the History of Medicine, Oxford, Wellcome Library in London, Epilepsy Research UK and Epilepsy Action, London.
My research will look into the role of the transcriptional repressor Spen in X inativation. Spen has already been found to be associated with the long non-coding RNA Xist that is known to mediate X inactivation by coating the surface of the inactive X chromosome. The nature of the interaction of Spen with Xist has not been investiagted in detail - the goal of my project is to characterise this interaction. My project will examine the importance of an RNA recognition motif (RRM) domain on the Spen protein, investigating its role in Xist binding. I will generate a mutant construct of Spen with the RRM domain of interest deleted, and examine its colocalisation with Xist. Xist will be expressed from an inducible promoter. The results of my project will generate data that will help to ascertain the importance of the RRM of Spen for Xist binding, helping to provide insights into the mechanism of X inactivation.
Laser capture microdissection to investigate bacterial handling defects in patients with monogenic inflammatory bowel disease 01 Apr 2016
Inflammatory bowel disease (IBD) is linked to defective bacterial handling in Crohn’s disease and monogenic diseases (Hugot et al. Nature 2001, Ogura et al. Nature 2002, Cooney et al. Nature Medicine 2010, Uhlig Gut 2013 and Uhlig et al. Gastroenterology 2014). Hypothesis: If defects in clearance of ingested bacteria cause granuloma formation we expect to find surviving bacteria (and its mRNA) in the granuloma lesions. Experimental Design Formalin-fixed archived tissue sections from patients with monogenic forms of IBD (XIAP , G6PC3 or HPS1) will be cut onto a capture membrane and stained with H&E. Granuloma will be isolated using laser capture micro dissection. 16S rRNA will be amplified using high fidelity PCR and sequenced. Comparison of the obtained sequences with public databases will establish which bacterial taxa. This project will help to identify bacteria that survive within macrophages and improve the understanding of the host-environment relationship.
Modelling the evolutionary epidemiology of chronic viral infections: Incorporating host heterogeneity into nested models of virus evolution 01 Apr 2016
One of the principal challenges in epidemiology is using mathematical models to plan disease control. This is made more challenging by pathogen evolution, which increases the complexity of disease dynamics, acting as a barrier to effective control. Chronic viruses such as HIV exhibit evolution over significantly shorter timescales than the long duration of infection. Understanding pathogen evolution and including it in models is therefore a key challenge for mathematical biologists. This project will explore how heterogeneity between hosts affects evolutionary dynamics at the population scale, building on a model in an existing paper that assumes that all hosts are identical. In this project, the model will be extended to include the heterogeneous immune responses to infection observed in different individuals. The dynamics of this new model will then be compared with the model in which all individuals are identical. Mathematical techniques required for this project include analysis of integro-differential equations (such as calculation of equilibria) and examination of the behaviour of integro-differential equations via numerical solution. The key goal is to develop a model of virus evolution that includes heterogeneous host types, and to investigate the evolutionary behaviour predicted by the model with different extents of host heterogeneity.
Acute myeloid leukaemia (AML) is a blood-related disease characterised by the uncontrolled proliferation of haematopoietic stem cells lacking the ability to commit to normal differentiation. It is highly malignant, with only a 25% survival rate 5 years after diagnosis, despite intensive therapeutic treatments. GATA2 is a zinc-finger (ZnF) transcription factor broadly expressed in haematopoietic stem cells (HSCs). GATA2 is necessary for maintenance of a regenerative HSC pool as well as lineage-restricted differentiation. Given this, it is perhaps unsurprising that GATA2 mutations have been linked with AML. Currently, little is known about the mechanism of GATA2 function in leukaemias. GATA2 contains 2 ZnF domains (NF and CF), which have been shown to bind different DNA motifs and protein partners in vivo. I postulate that these interactions are necessary for the biologial activity of GATA2, and will attempt to show that mutations in the NF and CF domains result in loss of this activity. This will be achieved by using a combination of methods including bioinformatics, molecular docking and in vitro biophysical studies using generated GATA2 mutants. This research aims to show that GATA2 mutants deregulate HSC proliferation by virtue of altering its ability to interact with cognate partners.
Members of the RIFIN family of Plasmodium falciparum are expressed on the surfaces of infected erythrocytes, where they are one of the few surface protein families exposed to the host immune system. They are members of a broader protein family, including the stevors, virs and pirs that are expressed across malaria parasites. This project aims towards the structure of the extracellular domain of a rifin protein, which will allow us to understand the architecture of this entire family of proteins. It also aims to understand the molecular basis for the interaction of a rifin with a novel class of antibody molecule with a LAIR1 insertion and to the molecular basis for the interaction of a rifin with a blood group A antigen. These studies will help us to understand the role of this enigmatic Plasmodium surface protein family that have been implicated in disease severity.
Identification of interferon-stimulated antiviral genes that contribute to the HIV-1 transmission bottleneck 01 Apr 2016
Identification of immune mechanisms of HIV-1 control at mucosal transmission sites is of importance to facilitate the development of strategies to block infection prior to systemic virus spread. My host lab have shown that HIV-1 transmitted founder viruses are relatively resistant to type I interferon (IFN)-mediated antiviral activity (as compared to viruses replicating in chronic infection), suggesting that type I IFNs make an important contribution to the HIV-1 transmission bottleneck. This project will contribute to ongoing work aiming to identify the IFN-stimulated antiviral genes that drive the IFN-resistance of founder viruses. My first aim will be to confirm preliminary results indicating that high concentrations of type II and III IFNs also inhibit HIV replication and that founder viruses are relatively resistant to their activity; and to test the effects of lower IFN concentrations. Findings from these experiments together with results from the lab’s microarray and qPCR-based analysis of common/differential gene up-regulation by high/low concentrations of type I, II and III IFNs will then be employed to identify genes to which founder viruses may be preferentially resistant. My second aim will be to use siRNA knockdown to test the role of 1-2 selected genes in founder virus IFN-resistance.