NIHRDataInsights/HRCSData huggingface dataset:
Title: Tissue-specific recruitment of regulatory T cells in colorectal cancer and liver metastases
Funder: Medical Research Council

Abstract: Aims: 1. Determine the expression and function of chemokine receptors and adhesion molecules on tumour-infiltrating Tregs compared to matched colonic tissue. 2. Define signals within the tumour stroma and parenchyma that results in localisation to specific compartments 3. Determine the frequency, distribution and function of dendritic cells (DC) in colorectal tumours and show how they maintain Treg survival and function at the tumour site. Methodology: * Tissue from colorectal primary and metastatic liver resections will be obtained from patients at the Queen Elizabeth Hospital, Birmingham. * Flow cytometry and intracellular cytokine staining will be used to phenotype lymphocyte subsets and determine expression of chemokine receptors and adhesion molecules. Real-time PCR will be used to quantify Mr.NA expression of adhesion molecules and chemokines. Positive findings will be confirmed by western blotting and immunohistochemistry. * Receptor function will be assessed using standard chemotaxis and adhesion assays. A flow-based adhesion assay will be used to prove function under conditions of shear stress. Real-time tracking of lymphocytes migrating into explanted CRC tissue slices will be performed using multi-colour confocal microscopy. * The phenotype and function of dendritic cells (DC) isolated from tumour and normal tissue will be assessed as well as their ability to induce and maintain a Treg phenotype by co-culture experiments. * Our laboratory data will be correlated with clinical outcome data to determine if expression of chemokine/adhesion molecules relates to outcome and survival. The information I generate will define the role of Treg recruitment in colorectal cancer, potentially leading to a novel therapeutic target.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS
Title: MICA: Whole body 3-D imaging of cancer and inflammation in live zebrafish using optical tomography and fluorescence lifetime readouts of signalling
Funder: Medical Research Council

Abstract: This project aims to develop and apply a new optical tomographic imaging platform to directly observe the progression of disease, including quantitative assays of morphological changes, physiological and molecular signalling processes in live whole juvenile and adult zebrafish that benefit from fully developed vasculature and immune system. We aim to extend optical projection tomography (OPT) to rapid imaging of cell migration using a novel (patent filed) configuration and realise 3-D mapping of optical absorption and fluorescence signals (including fluorescence lifetime imaging - FLIM) in cm-scale non-pigmented zebrafish lines using novel computational reconstruction algorithms to account for weakly scattered light propagation and ballistic light techniques to improve 3-D image quality. We will develop this technology in the context of its application to disease models for both cancer and inflammation. For this we will perform crosses and modify already available zebrafish strains, with fluorescently labelled vasculature and cell types (tumour cells, neutrophils and macrophages). For cancer we would make 3-D measurements of developing (inducible, syngeneic) tumours and the surrounding vasculature and map the localisation and size of resulting metastases over time. We would also read out the activation of Src, MT1-MMP & Rac biosensors using FLIM FRET and correlate changes in these important signalling pathways with tumour development. For inflammation we would image the kinetics of recruitment of inflammatory cell populations throughout a single fish in response to chemical pollutants and correlate this with the activation of signalling networks (Nalp3 inflammasome, TLR) using sensors for cathepsin B, caspase 1 and NF-kB. We would thereby study how chemically induced inflammation varies between larval, juvenile and adult zebrafish. As a basis for future projects, we would start exploring the inflammatory response in tumour bearing zebrafish.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS
Title: Isolation of a novel stimulator of adrenal steridogenesis from a gastrointestinal stromal tumour
Funder: The Dunhill Medical Trust

Abstract: A patient with ACTH-independent Cushing’s syndrome and bilateral nodular adrenal glands had an incidental finding of a gastrointestinal stromal tumour (GIST). We hypothesised that the GIST was secreting an agent which was causing adrenal gland stimulation and cortisol release, although there are no prior reports of this in the literature. The GIST was removed surgically along with one of the adrenal glands, and the patient’s Cushing’s was cured. A primary cell culture from the GIST tumor was established, and conditioned media (GCM) from this applied to the H295R adrenocortical cell line. Cortisol production from H295R cells incubated with GCM was significantly higher than control, and higher than cells stimulated with either ACTH or forskolin – the most potent in vitro stimulators of cortisol production in these cells. I aim to purify and identify the active factor from the conditioned media using chromatographic methods and mass spectrometric analysis, and to determine that pathway whereby it induces steroidogenesi


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS
Title: Stem Cell Centre Sorting Facility.
Funder: Wellcome Trust

Abstract: Research groups in the Institute for Biomedical Research (IBR) who are looking into the basic biology and therapeutic potential of stem cells have a continual need to be able to isolate highly purified cells from human and animal tissues. These cells are then used for direct analysis of their properties or for experimentation in animal models to determine how they might be utilised for tissue regeneration. The proteins present on their surface can define stem cells, and this can also be used i n their isolation if fluorescently tagged antibodies that bind to these proteins are used to mark the cells. Marked cells can then be passed through a machine that is able to separate them according to the amount of antibody bound. One such machine is already operating in the IBR, but the demands placed on it, from both stem cell biologists and others (mainly groups studying blood cells of the immune system), far exceeds its capacity resulting in long delays in being able to perform experiment s. This proposal is for the acquisition of a dedicated machine that will be used for sorting of stem cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS
Title: Identification of mechanisms underpinning neogenesis of high endothelial venules in tumours.
Funder: Wellcome Trust

Abstract: Studies of T cell mediated tolerance indicate that a subpopulation of T cells, named regulatory T cells (Tregs) serve as a major negative influence on the immune system. These cells, characterised by expression of CD4 and the transcription factor, Foxp3, keep both innate and adaptive immune responses in check and suppress responses to both self- and non-self antigens. A clear objective of Treg research is to determine how they can be manipulated therapeutically to treat a wide range of immune-ba sed diseases. In my laboratory we have found, using mouse models and studies of patients with cancer, that tumours represent a defined location of Treg enrichment. This finding highlights the utility of studying tumours for the purpose of identifying conditions and mechanisms that facilitate Treg involvement in disease. The key goal of this project is to use tumours to identify mechanisms that promote or inhibit the involvement of Tregs in a given immune response. This informat ion will subsequently be utilised in the design of strategies to block or enhance the activity of the cells for immunotherapeutic purposes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS
Title: Investigate the expression and function of the Tumour Necrosis Factor-related Apoptosis- inducing Ligand (TRAIL) on NK cells.
Funder: Wellcome Trust

Abstract: The immune system defends our organism from dangers such as infections and genomic mutations that can lead to cancer. In response to an injury, the immune system will initiate an inflammatory response that will resolve after repair hence preserving the integrity of our organism. In some circumstances, deregulation of the inflammatory responses lead to a persistent inflammation that causes pathologies such as autoimmune diseases. Over the past few years, researchers have found that instead of pro tecting the organism from the development of tumors, a chronic inflammation in a tissue can initiate and/or promote cancer development. This is why it is important to define the contexts influencing the immune system to participate in cancer progression as opposed to fighting it. The NK-receptors are molecules expressed by many immune cells contributing to the recognition and elimination of dangerous cells, such as cancer cells but not normal healthy cells. Our research studies will test the hyp othesis that in some circumstances, NK-receptors participate in the immune attack against normal cells in inflamed tissues, causing more damage consequently promoting the development of genomic mutations. Our goal is to understand the mechanisms that causes immunopathologies associated to chronic injuries such as autoimmune disorders and inflammation-related cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS
Title: Investigating the role of CXCR2 in pancreatic inflammation and cancer
Funder: Wellcome Trust

Abstract: Pancreatic cancer kills 7000 people per year in the UK. Aggressive progression makes early detection difficult. The disease is often too advanced for surgical treatment and tumours are resistant to chemotherapy. Chronic pancreatic inflammation predisposes to development of cancer. Pancreatic cancer interacts with immune cells to promote progression; the mechanisms by which this occurs remain ill-defined. CXCR2 is a cell signal receptor active in inflammation and tumour generation. One of CXCR 2s actions is to aid migration of inflammatory cells to the tumour environment. We aim to define the importance of CXCR2 in mediating inflammation around pancreatic tumours and confirm its importance in initiation and progression of the cancer. Mouse models of pancreatic disease will allow us to study this. By genetically removing CXCR2 we can determine its effect on inflammation, and pancreatic cancer. We will determine the expression levels of CXCR2 in mouse and human pancreatic cancer providi ng evidence to support examination in humans. Modulation of the immune system has been shown to be beneficial in studies of inflammation associated cancer. Should CXCR2 prove integral in the interaction between the immune system and pancreatic cancer in mediating progression, then it would represent an excellent target for future therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS
Title: Does enhanced PI3K signalling render APDS patients susceptible to infections by interfering with B cell development and activation?.
Funder: Wellcome Trust

Abstract: Defects in the immune system are responsible severe clinical problems in patients such as autoimmunity, immunodeficiencies and in some cases lymphoma or leukemia. We have identified a novel set of patients with a genetic defect that leads to antibody deficiency and cancer. Our project will investigate this defect in some of the immune cells (B cells) from the patients and in a mouse model. The gene defect leads to hyperactivity of the the PI3-kinase pathway inside the B cells,, and results in the disruption of the normal functions of cell. Drugs can inhibit PI3K pathway selectively in immune cells, offering the potential for effective and safe treatment. Our aim therefore is to understand exactly how this genetic defect leads to disease, and whether we can specifically target this pathway with new drugs in order to alleviate symptoms in our patients and eventually cure them. This is relevant not only to our group of patients, but might be applicable to others with similar problem s in B cells.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS
Title: Acquisition of a flow cytometry cell sorter
Funder: Wellcome Trust

Abstract: Fluorescence activating cell sorting (FACS) is specialised type of flow cytometry and allows one to isolate pure cell populations on the basis of surface markers from a heterogeneous mixture of biological cells. Specific cell populations can be discerned using multiple fluorescently conjugated antibodies which recognise specific markers expressed on the cell surface of cells, and on the basis of surface expression of multiple surface markers defined population can be easily sorted or purified a t >95% purity. To determine the contribution of specific cell types to diseases, such as inflammation, cancer and respiratory illnesses a FACS flow cytometer is required to obtain sufficient amounts of purified cell types and study these cells ex vivo in the disease context. Queen s University Belfast is currently not equipped with a FACS flow cytometer and would like to procure such a machine as a technical tool to drive current research programmes within the School of Medicine, Dentistry and Biomedical Sciences. Access to such a machine would ultimately improve research in areas of mortality and illness which is the major focus of research centres within the university.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS;INFECTION
Title: Identifying forms of thalidomide with clinical relevance for anti-inflammatory treatments with no teratogenic side-effects
Funder: Wellcome Trust

Abstract: Thalidomide is an extremely useful and powerful drug for a variety of clinical conditions, including leprosy and multiple myeloma. However thalidomide still causes birth defects when erroneously taken by pregnant women even today (particularly in Africa and South America). I wish to identify clinically relevant analogs of thalidomide that are non-teratogenic and further understand the mechanism/s by which thalidomide can be (i) teratogenic and (ii) protective against leprosy and multiple myeloma.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS;INFECTION
Title: CD8 coreceptor mediated optimization of the antigen specific T cell response.
Funder: Wellcome Trust

Abstract: The immune system contains killer T-cells which have a very potent ability to destroy infected cells and cancer. The ability of killer T-cells to perform this role makes them essential for clearance of many viruses and cancers. However, killer T-cells can struggle to recognize and destroy abnormal cells within the body. Killer cells work by recognizing tiny fragments of abnormal proteins at the surface of infected or cancerous cells using their own unique T-cell receptor. Killer T-cells also exp ress another protein called the CD8 coreceptor which can enhance their role in recognizing dangers by up to 1 million fold. Our goal is to examine whether we can improve the immune response to viral infections and cancer cells using the CD8 coreceptor. Such improvements could then be applied to boost immunity to any infection or cancer. All killer T-cells express an identical CD8 molecule; therefore using CD8 to optimize the immune response can be applied to any situation in which enhanced immun ity is desirable.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS;INFECTION
Title: The ubiquitin-dependent activation of kinases
Funder: Medical Research Council

Abstract: My research aim is to determine the molecular details of the polyubiquitin-dependent regulation of key kinase signalling complexes. Two families of kinases, the TAB1-TAK1-TAB2/3 (TAK1-TAB complex) and the inhibitor of kappa B kinase (IKKa/b) families, reside at the convergence of several pathways responsible for NFkB transcription factor activation, mediating expression of cell survival and pro-inflammatory genes. Other IKK-related kinases are involved in inflammation but are also important for selective autophagy and anti-viral signalling. Each of the aforementioned kinases is essential for correct signalling, and defects in their activity are associated with inflammatory diseases, certain cancers and also neurodegenerative diseases. Activation of TAK1 and IKK kinases is achieved by binding of adaptor proteins, which in turn are regulated by polyubiquitin chain binding to their ubiquitin binding domains. The fundamental question of how polyubiquitin binding to an adaptor molecule transmits a conformational change resulting in kinase activation, remains unknown. Given the pivotal role of these kinases in crucial signalling pathways, understanding the mechanisms of activation is of significant importance. I will reconstitute over-expressed kinase complexes from insect cells. Subsequently, I will utilise a toolkit of biochemical and biophysical techniques to investigate the stoichiometry, binding and kinetic parameters of kinase complexes. Additionally, I will use TIRF microscopy to investigate the order of kinase and adaptor recruitment to polyubiquitin chains. With these characterised complexes, I shall employ single particle cryo electron microscopy to obtain molecular details of kinase activation. In addition, the insights gained from these biochemical and structural analyses will be applied to cell-based and organism-based models, providing a complete analysis of this ubiquitin-mediated regulation from molecules to cells to whole organisms.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS;NEUROLOGICAL
Title: Natural killer cell migration in pregnancy and immunosurveillance regulated by PI3K
Funder: Medical Research Council

Abstract: Natural killer (NK) cells are lymphocytes that reside mostly in the vasculature of lymphoid and non-lymphoid organs, participating in reproductive success, regulation of immune responses and in immunological surveillance of cancer and infections. The functional versatility of NK cells is the result of subset heterogeneity and depends on appropriate location. Yet little is known about the factors governing NK cell trafficking and extravasation. This is historically due to the lack of appropriate tools, including those permitting in situ identification and in vivo tracking of NK cells. Both of these critical tools have now been developed and are available in our laboratory. The lipid enzymes of the phosphoinositide 3-kinase (PI3K) family regulate cell survival, growth, metabolism and motility, and we have highlighted unique roles played by the p110delta isoform of class 1A PI3K (p110d) in NK cell migration, differentiation, cytokine secretion and tumour rejection. Furthermore, we have completed the first analysis of the receptor repertoire expressed on mouse uterine NK cells and identified receptor-ligand interactions essential for NK cell mediated recognition of melanoma cells. We now wish to test the hypothesis that p110d regulates NK cell migration and we seek to better understand the mechanisms of NK cell extravasation and the downstream consequences on health and disease. The project is structured in three sections, that aim (I) to dissect the NK cell-autonomous mechanisms of extravasation regulated by p110d, (II) to explore the downstream consequences on immunosurveillance of melanoma and (III) to determine how PI3K contributes to the uterine NK cell repertoire and function during healthy placental development and fetal growth.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: A prospective randomised phase III clinical trial of rivaroxaban, a new fixed-dose oral anticoagulant, versus warfarin in patients with the thrombotic antiphospholipid syndrome, a complication of SLE
Funder: Arthritis Research UK

Abstract: The mainstay of the treatment of patients with the thrombotic antiphospholipid syndrome (APS), a complication of systemic lupus erythematosus (SLE), is warfarin. However, uncertainty about the intensity of the anticoagulant effect of warfarin and instability of the INR (International Normalised Ratio) in these patients necessitates frequent INR monitoring which is inconvenient and costly, and is potentially associated with an increased risk of recurrent thrombosis or bleeding. New fixed-dose oral anticoagulants could offer more predictable and efficacious anticoagulant than warfarin in patients with SLE/APS. The primary aim of this Phase II/III prospective randomised controlled clinical trial of the new oral anticoagulant rivaroxaban versus warfarin in patients with SLE/APS associated with venous thromboembolism on long-term warfarin target INR 2.5, is to compare the dynamics of ex vivo thrombin generation, a key marker of thrombogenic potential and efficacy of anticoagulation, in the two patient groups. We will also assess bleeding, other adverse events, clinical efficacy of anticoagulation and compare quality of life. The ultimate aim of this trial is to proceed to large multicentre European / International industry-supported randomised controlled trials, to establish whether or not a new oral anticoagulant should be the standard of care for the treatment of patients with SLE/APS.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR