NIHRDataInsights/HRCSData huggingface dataset:
Title: Structural biology of influenza, energy metabolism and cancer epigenetics
Funder: The Francis Crick Institute

Abstract: The aim of our research is to use structural biology to probe the mechanisms of protein molecules fundamental to cellular and disease processes. Our main approach involves structure determination by x-ray crystallography and electron microscopy integrated with biochemical, biophysical and cell-biological experiments to facilitate and interpret our structural data. We work on protein complexes, and protein/protein or protein/ligand interactions that either involve chromatin regulatory mechanisms, such as methylation, or proteins important in major disease areas such as the surface glycoproteins of influenza virus or the major kinases complexes implicated in the development of type II diabetes. Wherever appropriate we seek to exploit our findings for pharmacological benefit through patenting and partnership, for example with MRCT. Our interest in chromatin regulation through post-translational modifications has led us into working on polycomb repressive complex 2 (PRC2) which contains a histone lysine methyltransferase, EZH2, that is strongly implicated in the development of prostate cancer. We are using protein chemistry, molecular biology and x-ray crystallography to address the molecular mechanism of this large protein complex, to understand regulation of its catalytic activity and targeting to specific chromatin sites. Our principle collaborator is with Prof Danny Reinberg, NYU School of Medicine. As part of our longstanding collaboration with Virologists at the Francis Crick Institute we are working on the structural and functional characterisation of the two principle surface glycoproteins of influenza; neuraminidase (NA) and hemagglutinin (HA). With NA we are working with MRCT to develop novel inhibitors of this enzyme to expand the current range of anti-virals effective against influenza (Tamiflu & Relenza). We are using x-ray crystallography to understand the basis of drug binding/specificity and the basis of resistance mutations. On HA we are using x-ray crystallography, single particle analysis techniques and biochemical and biophysical approaches to understand the basis of the specificity of host cell interactions. This work is closely informed by the work of the World Influenza Centre housed at the Francis Crick Institute and is an important contribution to the influenza surveillance effort. In a long-standing collaboration with Prof Dave Carling, MRC London Institute of Medical Sciences, we are investigating the mechanisms of the diabetes-associated kinases AMPK and LKB1. We are using protein chemistry, molecular biology and x-ray crystallography to determine the structure/function relationships that control the activation mechanisms in these enzymes with the ultimate aim of informing the development of novel drugs for targeting diabetes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE;INFECTION;METABOLIC AND ENDOCRINE
Title: Phase I/II study investigating safety and efficacy of adenovirus-specific T-cells given to high-risk paediatric patients post-HSCT to treat reactivation of ADV
Funder: Innovate UK

Abstract: Cell Medica and UCL Institute of Child Health Great Ormond Street Hospital for Children NHS Trust will undertake a Phase I/II clinical trial - ASPIRE (Adenovirus-Specific Paediatric Immune REconstitution). The study is designed to demonstrate the safety and efficacy of Cytovir ADV - Cell Medica’s adoptive cellular therapy for the treatment of adenovirus infections in paediatric patients following bone marrow transplant (allogeneic haematopoietic stem cell transplant or allo-HSCT). Adenovirus infections cause mortality in up to 30% of children in high risk patient populations following allo-HSCT and current antiviral drug therapies are of limited benefit. Adoptive cellular therapy has already shown promising results in preventing viral disease in patients receiving a bone marrow transplant Cell Medica will be study sponsor and will prepare their adenovirus specific T cell therapy products (Cytovir ADV) for patients being treated. Dr Waseem Qasim and Prof Bobby Gaspar of the UCL Institute of Child Health Great Ormond Street Hospital for Children NHS Trust are the study investigators.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.4 SURGERY
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Finalise the development of a novel HPV test technology through clinical study
Funder: Innovate UK

Abstract: Human papillomavirus (HPV) is one of the most common sexually transmitted infections (STI). Some, but not all, types of HPV can cause cervical cancer (high-risk HPV types, HR-HPV). Since early stage cervical carcinomas are nearly 100% curable, early detection is very important. Accurate molecular diagnosis is needed to inform patient management and follow-up treatment. However, current methods suffer from sub-optimal sensitivity, discrimination and/or complex hybridisation-based procedures. GeneFirst has developed a unique technology (Multiplex Probe Amplification) for sensitive type-specific detection of more than 15 targets (e.g. HR-HPV types) in a single closed tube reaction. In this project, we set out to analyse the clinical performance of this novel HPV molecular diagnostics test to identify patients who have HR-HPV. Such an assay would offer physicians better means to identify women at risk and optimise treatment strategies.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Targeting mRNA export pathways as a novel antiviral strategy for Kaposi’s sarcoma-associated herpesv
Funder: Worldwide Cancer Research

Abstract: <p>KSHV has recently been classified by an International Agency for Research on Cancer working group as a Group 1 carcinogen. Epidemiologic studies show that KSHV is the cause of Kaposi&rsquo;s sarcoma (KS) and is also associated with&nbsp;two other lymphoproliferative diseases. Today, the African AIDs epidemic has turned KS into an epidemic disease. KS is now the most common reported adult tumour in sub-Saharan Africa. Moreover, KS is a frequent complication in the development of malignancy after solid organ transplantation.</p> <p>At present, there is no specific KSHV antiviral or vaccine. KSHV lytic replication plays an important role in viral spread, tumourigenicity and pathogenesis. Therefore, inhibition of lytic replication may halt KS development and become an important strategy for the treatment of KSHV-associated diseases.</p> <p>One essential feature of KSHV lytic replication is the efficient nuclear export of the&nbsp;KSHV intronless mRNAs. To perform this function, KSHV encodes the ORF57 protein which orchestrates the assembly of an export competent viral ribo-nucleoprotein particle (vRNP). We have utilised a global proteomic-based pulldown approach to identify for the first time that the cellular proteins, SRAG and Cip29, are associated with the KSHV ORF57-mediated vRNP.</p> <p>We will investigate the role of SRAG and Cip29 in the formation of a KSHV ORF57-mediated vRNP and how they function to enhance KSHV intronless mRNA nuclear export. Moreover, we will determine whether&nbsp;ORF57-mediated vRNP formation&nbsp;can be targeted as a novel antiviral strategy. We will specifically inhibit the&nbsp;activity of a key vRNP component, UAP56, using low molecular weight inhibitors identified by a virtual high-throughput screening campaign. Selected compounds will then be tested for their ability to inhibit ORF57-mediated vRNP formation and KSHV lytic replication. If successful these compounds could form the basis for new antiviral strategies&nbsp;targeted against this&nbsp;important human pathogen.</p>


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: How do T lymphocytes control Kaposi’s sarcoma-associated herpesvirus infected cells?
Funder: Worldwide Cancer Research

Abstract: <p>Kaposi&rsquo;s sarcoma-associated herpesvirus (KSHV) causes Kaposi&rsquo;s sarcoma (KS), the most frequently reported neoplasm of HIV-infected patients and sub-Saharan Africans, and other proliferative disorders namely primary effusion lymphoma (PEL) and multicentric Castleman&rsquo;s disease.&nbsp; Compelling evidence suggests the T lymphocytes control infections and malignancies caused by this virus.&nbsp; The KSHV targets of the T cell response are likely to be the latent proteins the virus consistently expresses in these disorders including LANA, vFLIP, vCyclin and some others.&nbsp; We have identified T cell epitopes and established T cell clones specific for these three KSHV latency proteins.&nbsp; However, KSHV appears to use multilayered mechanisms to thwart T cell targeting and clearance.&nbsp; At least two latent proteins show features which may minimise CD8+ T cell recognition.&nbsp; We will test this by expressing these proteins and modified forms of them in target cells and examine KSHV-specific CD8+ T cell recognition, to determine whether targeting CD8+ T cells to these malignancies are likely to be viable interventions.&nbsp; As we suspect CD8+ T cell recognition may be inhibited, we will examine the ability of KSHV-specific CD4+, and also CD8+, T cells for their ability to recognise physiologically relevant KSHV-infected cells, namely B lymphocytes and endothelial cells.&nbsp; Here we wish to determine whether latent antigen-specific CD4+ T cells are better at controlling infected cells, particularly B cells, as CD4+ T cell recognition will less affected by KSHVs mechanisms which may reduce CD8 targeting.&nbsp; Finally we will investigate how KSHV interferes with the killing clearance mechanism in infected cells.&nbsp; We have previously found that although T cells could recognise some KSHV transformed cells (PELs) they could not kill them.&nbsp; We plan to identify if a KSHV latent protein is responsible for this and identify mechanisms by which we can restore sensitivity to T cell mediated killing.</p>


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Methyl donor status and oral HPV infection in young adults: importance to oropharyngeal cancer
Funder: World Cancer Research Fund

Abstract: Background: The incidence of oropharyngeal cancer in younger adults is increasing, especially cancer positive for human papillomavirus (HPV) infection. Oral HPV infection is a risk factor, independent of tobacco use and alcohol consumption. Research into


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Development Grant - Characterisation and assessment of the functional impact on gastric preneoplasia of the non-helicobacter gastric dysbiosis
Funder: CORE

Abstract: Stomach cancer has been linked to infection of the stomach with a bacterium called Helicobacter pylori. This infection is very common, up to half of the world’s population have been exposed to it at some point, however only a tiny percentage of people infected with H. pylori subsequently develop gastric cancer. This paradox shows that there are other factors that lead to an individual infected with H. pylori developing gastric cancer. Our laboratory has been investigating some of these factors. Most recently we have demonstrated that certain parts of the immune system, called NF-κB signalling pathways, regulate the development of gastric disease after infection with Helicobacter. We have shown that the suppression of a protein called NF-κB1 leads to more severe damage to the stomach lining after Helicobacter infection, whilst deletion of NF-κB2 protects against Helicobacter induced damage. Until recently it was thought that the healthy stomach was entirely sterile, but over the last few years it has become clear that a mixed population of bacteria live in close proximity to the stomach lining. Previous investigators have shown that when Helicobacter exists in complete isolation from other bacteria progression of the development of stomach cancers was delayed. This might suggest that changes in the composition of bacteria found in the stomach can actually influence whether an individual develops stomach cancer. In our work in addition to an altered susceptibility to Helicobacter induced disease we have also shown that the deletion of NF-κB proteins resulted in a change in the composition of other bacteria that were present in tissue samples from the stomach lining. This link between a part of the immune system and the variety of bacteria that live in close proximity to the lining cells of the gastrointestinal tract is of particular interest to us, since it could provide a mechanism through which an altered immune system could influence the risk of progression to stomach cancer. CORE has provided funding for us to continue to explore in more detail how the link between the NF-κB system and changes in the composition of bacteria that live in the stomach influence the progression of stomach cancer. With this grant we will be able to determine with more precision how the bacteria in the stomach are altered when NF-κB proteins are deleted, and whether inducing an altered bacterial composition in the stomach of a normal individual is sufficient to alter the eventual outcome of Helicobacter infection.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Analysis and Exploitation of Oxygen-Dependent Modification to Ribosomes
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Ribosomes are intracellular machines that make proteins, but they also contain proteins. Recent BBSRC funded work led to the discovery that ribosomal proteins undergo a modification, termed hydroxylation, dependent on atmospheric oxygen at sites of importance for protein biosynthesis. One of the largest classes of antibiotics, e.g. erythromycin, targets ribosomes. Point mutations to ribosomes confer resistance to such antibiotics. Hence it should be possible to develop compounds that selectively target unmodified over modified ribosomes. Tumour cells are often hypoxic so should contain ribosomes that are ales hydroxylated than normal cells. We propose to use Follow on Funding to test synthetically modified antibiotics (guided by ribosome structures) to identify compounds that selectively inhibit unmodified over modified (or vice versa) ribosomes. The results will be used to support patent applications and, if appropriate, to form a spin-out company.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Investigate the role of avian viral diseases in the modification of host epigenetic factors and translational control
Funder: Biotechnology and Biological Sciences Research Council

Abstract: To establish the tools and resources that are specific for research into the field of avian epigenetics. Whilst many of the proteins that are crucial are highly conserved and therefore cross-react with tools developed for human/mouse research, many proteins will be different enough to not be conserved. The techniques that will be used to investigate this include MeDIP (methylated DNA immunoprecipitation) and bisulphate sequencing to investigate methylation status of the DNA. I will also develop further Chromatin Immunoprecipitation (ChIP) and qPCR analysis along with ChIP-on-chip or ChIP-seq (ChIP, coupled with deep-sequencing analysis). Focus these efforts onto avian diseases, such as MD to give a high fidelity epigenetic map of primary tumours and cell lines of both the viral and host chromatin. Also apply these techniques to untransformed cells. These can be taken from peripheral blood through cell sorting, or by looking at the differentiation of stem cells. The elucidation of genes and regions that are influenced by the viral pathogens will allow a more targeted approach to understand the changes in translation and epigenetics marks by investigating changes in translation of specific initiation factors, elongation of poly-A modifications on these genes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Scottish Cervical Cancer Prevention Programme: Establishing an HPV Clinical Research Centre for long-term follow-up of HPV infection and associated disease in a vaccination era, through the creation of a population based sample archive.
Funder: Chief Scientist Office (Scotland)

Abstract: HPV immunisation was introduced in Scotland in September 2008. We plan to establish an HPV Clinical Research Centre and Research Network which would build on Scotland’s strengths in data linkage, stable population base and cervical screening programme which begins at age 20. Research undertaken now will gain significant time advantage compared with other national programmes. A key target is the creation of an archive of LBC samples from 50,000 women attending first or second cervical screen linked to national vaccination and clinical datasets through CHI numbers. This will produce the largest known curation of cervical samples and provide a useful resource for future studies. We will develop new HPV typing methodologies; assays for non-interventional samples suitable for cervical cancer prevention in a post vaccine era and HPV test defined cohorts to determine shifting patterns of HPV infection. Outcomes will inform future health policy decisions on HPV vaccination and changes required for cervical screening.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: HPV Oral Prevalence in Scotland (HOPSCOTCH) Feasibility Study
Funder: Chief Scientist Office (Scotland)

Abstract: Human Papilloma Virus (HPV) infection is increasingly implicated in the rising incidence of oral/oropharyngeal cancer, which is the fastest increasing cancer in Scotland, especially in men. However, little is known about the extent, transmission, and determinants of oral HPV infection. Recent data (Sept 2012) show that over 90% of 12-13 year-olds and 65% 14-18 year-old females have received the HPV vaccination in Scotland since 2008, to prevent cervical cancer. However, the vaccine’s impact on oral HPV in females, and “herd immunity” in males is unknown. We aim to test the feasibility of conducting a full population-based investigation into the prevalence and incidence of oral HPV in Scotland to inform preventive programmes. This feasibility study will test: (i) suitability/uptake of dental settings / different models of recruitment; (ii) subject participation/consent/follow-up; (iii) data and specimen collection - including lifestyle/sexual history questionnaire, oral rinse; (iv) record-linkage; (v) HPV assay validation.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: Methodology for, and Synthesis of Biologically Active Pyrrolidinone Natural Products.
Funder: Engineering and Physical Sciences Research Council

Abstract: Five-membered ring compounds with contain one nitrogen atom, are ubiquitous structural units present on thousands of natural products, in numerous brand-name drugs and agrochemicals, and are widely used to modify catalysts for a particular purpose. These nitrogen "heterocycles" are present in a family of highly complex natural products which exhibit antitumour and antibiotic activity. The search for new antibiotics is particularly important now we are in the "post-penicillin" era and our entering the era when even resistance to antibiotics such as vancomycin is regularly encountered. The search for new antibiotics with different modes of action is an important challenge facing academia and the pharmaceutical industry. The aim of our work is to develop new and efficient methods for the synthesis of nitrogen heterocycles which will have particular application to the synthesis of these antitumour antibiotics. A major part of the project will involve using the developed methodologies to synthesise one of the natural products and, importantly, to prepare simplified analogues. The simplified analogues will be tested for both antibiotic and antitumour activity. In the long term, this research may have an impact on the discovery of new antibiotics and antitumour agents. Moreover, the developed methodologies will have application in the synthesis of a whole range of other biologically important natural products and small molecules.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;INFECTION
Title: High-throughput Optical Blood Imaging for the Detection of Rare Cells using Ultrasonic Particle Alignment
Funder: Engineering and Physical Sciences Research Council

Abstract: Millions of blood samples are analysed in the NHS every year. A wide range of parameters are measured, however there are significant limitations with existing technologies, particularly those relating to the detection of rare cells and bacteria in the blood in a way that permits timely medical intervention. Modern computers have the power to examine images of billions of blood cells, and flag up those of interest. However, taking images of the cells individually (as is done in some existing machines) is not fast enough, being limited to a few thousand cells per second. In this project we will flow a sample of blood through a tiny chamber and use ultrasound to align all the cells into a single sheet; this key step means that it will be possible for a microscope to take an image of thousands of the cells at once. In this way we predict it will be possible to image around 50,000 cells per second. Without this acoustic focussing, the cells would not all be in focus, and many would overlap with each other. Working with our partners at Southampton hospital, we shall initially test our system by looking for cancer cells in the blood. Recent research has shown that individual cells from a cancer can become detached and enter the blood stream, and it is in this way that cancers spread to different areas of the body (metastasize). These cells are present in very small numbers - in 10 ml of blood even one tumour cell hidden amongst billions of normal cells could indicate a cancer. Later on in the project we will also consider looking at leukaemia cells, parasite infections (such as malaria), and potentially bacterial infections. There are several challenges facing the project including creating an ultrasonic force field that is both strong and uniformly focussed, the difficulties of capturing images of the moving stream of blood cells without motion blur, and integrating the image processing to deal with the huge amounts of data that will be produced. The different applications we consider vary enormously in the challenge they present, ranging from the tiny and difficult to manipulate bacteria, through to the much more numerous malaria parasites inside red blood cells. Given the huge potential health benefits of having our systems made widely available, we will work closely with industrial companies that have experience of creating diagnostic machines to bring our technology into widespread use as soon as possible. Into the future we see many further developments, including systems that are able to capture the rare cells as they are detected, and collaborative research projects with clinical scientists to use our devices to enable new insights into the workings of diseases.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS;INFECTION