NIHRDataInsights/HRCSData huggingface dataset:
Title: Proof of principle: human embryonic stem cell derived red cell concentrates for clinical transfusion.
Funder: Wellcome Trust

Abstract: Blood Transfusion has become a mainstay of modern medical practice. However problems persist both nationally and internationally in maintaining adequacy of supply, managing the risk of transmission of infectious agents and ensuring immune compatibility between donor and recipient. Human embryonic stem cells (hESCs) have unique properties in that they can be maintained indefinitely in culture in an undifferentiated state and yet retain the ability to form all the cells and tissues within the body. They therefore offer a potentially limitless source from which to generate red cells for use in clinical transfusion. We have the capability to generate hESC to cGMP grade in compliance with UK regulatory requirements for eventual clinical use. We intend to differentiate these to form haematopoietic progenitor cells (HPC). We will subsequently differentiate these down the erythroid lineage. The resultant red cells will be evaluated in terms of their morphological, immunohaematological and rheological characteristics. We will scale the process to produce 2 x10 (power of 12) red cells per batch, approximately the equivalent of a standard red cell concentrate. Leucocyte filtration will be used to separate the nucleated cells from the red cells, the latter will be used for follow-on proof of principle clinical safety and recovery studies.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: The early events in signalling by platelet ITAM and ITAM-like receptors.
Funder: Wellcome Trust

Abstract: Platelets are small cells in the bloodstream that clump together at sites of injury to form a vascular plug and prevent excessive bleeding. The same events in diseased blood vessels lead to thrombotic disorders such as stroke and heart attack, which are a major cause of mortality in the western world. This application concerns the investigation of a unique pathway of activation of platelets, known as an ITAM pathway, which plays a critical role in platelet activation and platelet disorders, in cluding thrombosis, cancer and snake bite. We believe activation of platelets through this pathway plays additional roles in the body, including the development of the lymphatic system which returns fluid that has leaked into tissues to the bloodstream. The increased understanding of these events will tell us more information about the role of platelets in the body and may identify new targets for the development of antiplatelet drugs in the fight against thrombosis, cancer and other disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: Biogenesis of the red blood cell cytoskeleton in health and disease
Funder: Wellcome Trust

Abstract: To investigate the expression, associations and localisation of key erythroid cytoskeletal proteins during erythropoiesis. - To determine the role of the erythroid cytoskeleton in protein sorting during enucleation - To understand the mechanism by which cytoskeletal changes result in human red blood cell diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: The role of anaemia and foetal haemoglobin in Sickle Cell Disease: Clinical epidemiology to establish the evidence base for interventional trials of blood transfusion and Hydroxyurea.
Funder: Wellcome Trust

Abstract: Severe anaemia is a major cause of morbidity and mortality in SCA. HbF is a major factor influencing anaemia, BT requirement and outcome. There is no information on HbF in East Africa. I propose to examine the association of HbF and severe anaemia in Tanzanian SCA patients. BT is the mainstay of management but concerns about safety, supply and cost have prompted a search for alternative interventions. Hydroxyurea is used in SCA in North America and Europe; effectively reducing morbidity (pain , hospitalisation, BT) and mortality. Its main efficacy is increasing HbF levels, but this has not been consistently reported. Other mechanisms include reduced inflammation and vasculopathy. There is inadequate information on its efficacy, mechanism of action and safety in Africa as it would be an alternative for BT. I will describe the response to hydroxyurea in SCA; determine the toxicity, optimal dosing and monitoring regime. In identifying patients for hydroxyurea treatment, I will dete rmine and treat known causes of severe anaemia such as infections (malaria, bacteraemia, parvovirus), splenic sequestration and nutritional deficiency (folic acid, vitamin A, B12, iron). This fellowship will provide the evidence on HbF and hydroxyurea required to conduct clinical trials and improve management of severe anaemia.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: BLOOD
Title: Biogenesis of the red blood cell membrane in health and disease.
Funder: Wellcome Trust

Abstract: In the bone marrow, red blood cells are constantly being produced from progenitor cells, a process called erythropoiesis. During erythropoiesis, progenitors undergo a remarkable transformation; they become smaller, lose their nucleus and remodel their membrane to generate the biconcave red blood cell. Throughout this process, a network of membrane protein complexes must be assembled and retained to enable the red blood cell to conduct its crucial role of carrying gases around the body. Changes i n the composition of these membrane complexes alter the antigenic profile, shape, cell stability and can cause anaemia. We have developed a culture model that mimics how blood cells develop to enable us to study when the key interactions are formed and how this goes wrong in human disease. We are currently in a unique position to compare the composition and assembly of normal protein complexes to those found in patients with defective red blood cells. We will study the role of specific proteins using biochemical and cell biology techniques during erythropoiesis and explore how we can manipulate the assembly of protein complexes for the benefit of patients.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD
Title: Development of a ready-to-use nutraceutical food for patients with sickle cell disease (SCD) : testing of vascular support components.
Funder: Wellcome Trust

Abstract: Sickle cell disease (SCD) is the most common inherited disorder worldwide affecting 300,000 births annually, most occuring in sub-Saharan Africa (SSA) where poor detection and care result in high childhood mortality, malnutrition, illness and disability in survivors. SCD is caused by abnormal haemoglobin, the compound in red blood cells (RBC) that carries oxygen. Much of the disability is caused by vascular damage from the breakdown of damaged RBC. Research in high-income countries has led to so me effective therapies but these are currently costly and complex. We will develop an affordable, ready-to-use supplementary food (RUSF) specifically tailored for SCD children.As well as containing energy, protein, essential fats, vitamins and minerals, the RUSF will be fortified with the amino-acids arginine and citrulline and co-packaged with the anti-malarial chloroquine to create a novel nutraceutical food. Arginine is converted to nitric oxide which is essential for vascular health. Ar ginine levels are low in SCD because the arginine-degrading enzyme,arginase, is released from RBCs. We propose that by supplying additional arginine (and citrulline which converts to arginine) and suppressing arginase activity (an action of chloroquine) we can improve vascular function. Our study will test this theory, and if provision of RUSF improves growth.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: BLOOD
Title: Immune consequences of red cell ageing, death and disposal
Funder: Wellcome Trust

Abstract: Red blood cells (RBC), like most other cell types, are continually removed and replaced in healthy people. The consequences of accelerated removal are important, but poorly understood, in many diseases that damage RBC, including sickle cell disease, malaria and autoimmune haemolytic anaemia. Accelerated RBC removal can also cause serious complications in patients receiving transfusions, and there is an urgent need to understand how this risk increases with routine storage of blood. The effect s of RBC removal may be driven via the immune cells that clear them from the circulation, and this programme aims to understand these immunological consequences for the first time. The goals are to discover the effects of RBC uptake on the clearing cells; establish how these effects are modified by storage of transfused blood; identify the changes to RBC that are responsible; map the precise anatomical site and type of cell mediating clearance in life; and determine the immune effects of abnorm al clearance in patients with disease. This application builds on ongoing partnership between the University of Aberdeen and the Scottish National Blood Transfusion Service, together with key collaborations. The results will be of direct clinical relevance, as well as informing knowledge of cell turnover more generally.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD
Title: Identifying novel therapeutics and disease mechanisms for ribosomal-protein mediated human haematopoietic disease: Award of a Wellcome-Beit Prize.
Funder: Wellcome Trust

Abstract: My research project uses embryos from zebrafish, a simple vertebrate organism to model two genetically related but clinically distinct conditions, myelodysplasia with loss of 5q and Diamond-Blackfan anaemia. The pathophysiology of these conditions is thought to be related because both result in anaemia associated with ribosomal protein haploinsufficiency. In Aim 1 I use an innovative adaptation of Illumina next generation sequencing technology to identify specific alterations in translational ca pacity in ribosome protein haploinsufficiency. Detailed analysis of this data will prioritise genes/proteins for further study in primary human cells from normal donors (initially) and patient samples. In the second Aim I will screen in vivo for novel compounds that improve the anaemia associated with ribosomal protein deficiencies (myelodysplastic syndrome (RPS14) and Diamond-Blackfan Anaemia (RPS19 and others)). The libraries being applied to the zebrafish embryos will initially be compounds w hich are approved for clinical use. This will facilitate the translation to primary human samples (in this project) and clinical trials (in later projects). The key goal of this study are to provide an unprecedented depth of knowledge about the biological effects of ribosomal protein loss which will inform our understanding of the disease mechanism as well as providing novel therapeutic targets.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: Identifying novel therapeutics and disease mechanisms for ribosomal-protein mediated human haematopoietic diseases.
Funder: Wellcome Trust

Abstract: Recent research has identified a common link between two diseases that have abnormal red blood cell production (anaemia), myelodysplastic syndrome (MDS) and Diamond-Blackfan Anaemia (DBA). These diseases are quite different - DBA is a rare inherited disease while MDS is a common disease usually affecting older patients, but both appear to occur from a defect in the bodies protein-making machinery. How and why this defect effects blood cells is not known. The only curative treatment these conditi ons is a stem cell transplantation (SCT). SCTs require a suitable donor and are often associated with severe side effects, which makes them unsuitable treatments for many children and adults. This research aims to identify new therapies that will be effective for treating both diseases, and to understand more about how and why the anaemia occurs. We believe this research will provide us with a greater understanding of these conditions and help identify better treatments, to improve the long term survival and quality of life for patients with DBA and MDS.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: A new approach for linking enhancers to specific promoters.
Funder: Wellcome Trust

Abstract: Following completion of the Human Genome Project it has been found that many mammalian genes are regulated by distant regulatory elements, which may lie hundreds of thousands of nucleotides away from the genes they control. Establishing which regulatory elements control which genes is a key stumbling block in deciphering the genome. These regulatory elements loop to physically interact with the gene to alter transcription. The host laboratory has recently developed a technique called cap ture 4C, which allows the regulatory elements of the multiple genes to be identified simultaneously. This technique combines chromosome conformation capture with a DNA capture system and high throughput sequencing and it has significant advantages over previous methods. The project aims to identify the regulatory elements of 20 genes that control red blood cell formation and investigate how the interactions between the regulatory elements and genes change as blood stem cells develop into red cells. The project will then investigate how DNA sequence changes (polymorphisms) in regulatory elements alter gene expression. Elucidation of the principles by which genes are switched on and off using red cells as a model, will give insight into how differences in DNA sequences predispose individuals to common diseases including diabetes and hypertension.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD
Title: Scalable in vitro production of red cells for clinical transfusion.
Funder: Wellcome Trust

Abstract: Creating the ability to manufacture cultured red blood cells (cRBC) from stem cell lines is an important step towards solving supply shortages and reducing the risks of mismatched blood and transfusion transmitted infection in many countries. There is also increasing evidence that red cells stored for longer periods may have harmful effects in ill patients. cRBC are likely to contain a higher proportion of younger cells than standard donated red cell concentrates and may, therefore, provide cl inical advantages by surviving longer and performing better. Over the past 4 years with the support of the Wellcome Trust, we have established a clinical grade Good Manufacturing Practice protocol for using stem cell lines to manufacture red blood cells. We will build on this work to address 3 key issues: (i) improve and perfect this protocol, (ii) expand the manufacturing capacity (iii) conduct preclinical assessment and gain regulatory approval for initial studies in human volunteers. This w ork will provide the basis to attract investment for the development of large-scale manufacturing capability and clinical studies. Our first clinical and commercial target will be treatment of chronic transfusion-dependent beta thalassaemia, where the complications associated with regular transfusion of red cells cause significant premature death world-wide.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD
Title: Therapeutic targeting of HIF prolyl hydroxylases in acute myeloid leukaemia
Funder: Medical Research Council

Abstract: Acute myeloid leukaemia (AML) is a clonal disorder of haematopoietic stem cells (HSCs) and progenitor cells, which acquire mutations and form treatment-resistant leukaemic stem cells (LSCs) that propagate the disease. Since current therapies often fail to fully eradicate LSCs, it is essential to identify new therapeutic targets for LSC elimination. Considering that normal and malignant haematopoiesis occur under hypoxic conditions of the bone marrow, we investigated the role of hypoxia-inducible factor-1alpha (Hif-1alpha) and Hif-2alpha, the main mediators of cellular responses to hypoxia, in these processes. We found that while HSCs do not require Hif-1alpha and Hif-2alpha to self-renew and sustain haematopoiesis (Guitart et al., Blood, 2013 and Vukovic et al., Blood, 2016), Hif-1alpha and Hif-2alpha synergise to suppress development and maintenance of LSCs in several mouse models of AML (Vukovic et al., J. Exp. Med., 2015). We now intend to investigate the therapeutic significance of a constitutive activation of Hif-1/Hif-2 in AML. Firstly, we will delete or suppress Phd2 (a Hif prolyl hydroxylase whose activity normally results in Hif-1/2alpha degradation) in different mouse models of AML and test the impact of this manipulation on the development and maintenance of LSCs. Secondly, we will establish the therapeutic potential of pharmacological Phd2 inhibition in mouse AML models and immunocompromised mice xenografted with different subtypes of human AML. Finally, we will identify and functionally validate the mechanisms through which Phd2 inactivation compromises LSC functions. This project will validate Phd2 as a therapeutic target in AML and reveal further Hif-dependent targets for LSC eradication. We will next be in a position to harness this knowledge to design improved treatment regimens in AML and test them in clinical trials.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: BLOOD;CANCER AND NEOPLASMS
Title: Human normal and malignant haematopoietic stem cells and their microenvironment
Funder: The Francis Crick Institute

Abstract: Haematopoietic stem cells (HSC) sustain the life-long maintenance of mature blood cells. They reside in the bone marrow (BM) cavity, where they interact with different types of stromal cells. Our group is interested in understanding the mechanisms regulating human haematopoietic stem cells (HSCs), both in normal development and during leukaemia. Over the past decade or so, work from different groups, has allowed to better define the contribution of different stromal cells in the maintenance of HSCs in the BM. Much less is known about the modulations/modifications in microenvironment “factors” that are occurring during leukaemia transformation. Our group is particularly interested in dissecting the cross-talk between normal and leukemic stem cells and their microenvironment. We thus make use of the xenotransplantation model to functionally study these cells and their interactions with the bone marrow niche. We used intra-vital imaging techniques in order to visualise HSC and Leukaemia stem cell (LSC) in their microenvironment and live time-lapse imaging to follow their motility behaviour. We have also recently developed a new 3D scaffold culture system where human stroma cells could be co-cultured with human normal HSC or LSC to study the mechanisms of interaction between normal and/or leukemic stem cells and their niche. Using RNA sequencing we are dissecting the molecular mechanisms by which leukemic cells modulate their own microenvironment. By elucidating the above microenvironment features involved in leukemic development, this project has the ultimate purpose of improving current anti-leukemic therapeutic protocols by providing new directions for clinical research for better disease prevention, therapy development. Investment in this field of research is likely to contribute to improve quality of life of leukemic patients and to reduce mortality. Furthermore, as certain microenvironment perturbations seen in myeloid malignancies are generally seen in other solid cancers, knowledge gained in this project potentially has a broader impact in the treatment of cancer patients


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;CANCER AND NEOPLASMS
Title: Haematopoiesis - Novel tools for modelling normal and perturbed haematopoiesis
Funder: Medical Research Council

Abstract: Despite remarkable progress in the transcriptional and genomic profiling of normal and diseased blood cells, an urgent need exists to develop tools that will permit the dissection of the cellular and molecular mechanisms underpinning normal haematopoiesis and its responses to stress and disease. Tools to accurately map the cellular identity of specific haematopoietic cell subsets in vivo are regularly lacking and even fewer tools exist to selectively manipulate the expression of multiple genes in specific target cells in the correct spatio-temporal manner. Building on our extensive transcriptomic and genomic datasets from normal, post-infection and pre-leukaemic cells in patients and mouse models, our cluster will work with the Mary Lyon Centre to develop next-generation mouse models, harnessing restricted intersectional recombinase gene expression to precisely map and manipulate haematopoietic cells. Specifically, our work will focus on three key areas: 1) new tools to mark and target unique haematopoietic cell types 2) Improved modelling of complex disease in haematological malignancies with respect to mutation timing and cell of origin and 3) New tools to specifically target normal and diseases cells during development.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: BLOOD;CANCER AND NEOPLASMS
Title: Biology and Treatment of Human Myeloid Cancers
Funder: Medical Research Council

Abstract: Approximately 10 billion new, polyclonal, human myeloid blood cells terminally differentiate daily. We aim to understand mechanisms by which recurrent genetic mutations, epigenetic change, and an altered microenvironment, subtly disrupt this differentiation cascade causing clonal haemopoiesis of indeterminant potential (CHIP) initially, and then the clinical disorders, myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). Over the last 5 years, we have defi ned aspects of the complex normal hierarchy of early human blood stem/progenitor cells. We have purifi ed and characterised the transcriptional profi les of functional AML leukaemic stem cells and shown they are arrested at progenitor and precursor stages of haemopoiesis. We have functionally tested the spectrum of oncogenic mutations that lead to AML transformation. Finally, we have used this information, and sequential human bone marrow samples, interrogated by single cell analyses, to understand how therapy modulates the clonal landscape of preleukaemic and leukaemic clones leading to AML therapy response and therapy failure. This is vital information to develop new rational therapy combinations. Over the next 5 years, we will determine the timing of acquisition of mutations causing CHIP, and the timing of mutations associated with with MDS and transformation to AML. Using human samples and mouse models, we will model the quantitative advantage conferred by CHIP/MDS/AML mutations to mutant blood stem cells, and the impact sequential genetic mutations, and epigenetic changes on differentiation that causes MDS and transformation to AML. Finally, we have an ambitious program to develop novel immune therapies in AML.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;CANCER AND NEOPLASMS