NIHRDataInsights/HRCSData huggingface dataset:
Title: Assessing the tolerability of a potentially safer radical curative regimen of primaquine in healthy volunteers with glucose 6 phosphate dehydrogenase
Funder: Medical Research Council

Abstract: Relapse is the main cause of Plasmodium vivax malaria illness. Prevention of relapse and ultimately elimination of P. vivax can be achieved only by killing the liver stage parasites (hypnozoites) that cause relapse. Primaquine (PQ) is currently the only registered hypnozoitocidal drug but it causes acute haemolysis in glucose-6-phosphate dehydrogenase deficiency (G6PDd), the most common enzymopathy of man (prevalence up to 30%). As G6PD testing is generally unavailable radical cure with primaquine is seldom used. PQ haemolyses older more G6PD deficient red cells so controlled haemolysis allows gradual replacement of vulnerable erythrocytes without dangerous anaemia. Based on studies in the mild G6PDd (African) A- variant, 0.75 mg PQ/kg/week for 8 weeks is recommended by WHO for radical cure in G6PDd, however this regimen may be unsafe in the more severe variants prevalent outside Africa. A safer regimen, not requiring G6PD testing, would be a major advance. Using all available data, we developed a mathematical model of red cell dynamics. It suggests an ascending PQ regimen of four 5 day cycles (7.5, 15, 22.5, then 30 mg/day) would provide a gradual and safe haemoglobin (Hb) decline because haemolysis of older cells induces reticulocytosis and these young cells are resistant to oxidant haemolysis. The total PQ dose, 6.25 mg/kg, approximates the 7 mg/kg recommended for tropical P. vivax. We propose an adaptive Phase 1-type, dose finding study designed to maximise safety in healthy G6PDd Mahidol or Viangchan variant Thai adults. In 5 cohorts of five, the 1st cohort will receive the modelled regimen which may be modified in the next cohort following a pre-specified Hb response algorithm. If this trial is successful, we will: (i) proceed to a safety and efficacy study in G6PDd vivax patients, and (ii) design an adaptive trial for the severe G6PDdMed variant. We aim to provide safer immediately deployable antirelapse regimens that do not require G6PDd testing.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: BLOOD;INFECTION
Title: Creation of a novel monitoring tool to predict abnormal coagulation in COVID-19.
Funder: Innovate UK

Abstract: The formation of blood clots has been identified as a potential risk factor for a very small proportion of individuals receiving certain types of COVID-19 vaccine. A larger proportion of people who have tested positive for COVID-19 (the infectious disease caused by the coronavirus) have also experienced inappropriate blood clotting, which has resulted in more severe symptoms and unfortunately, been associated with a higher risk of virus-related death. ProAxsis is a Belfast-based company, specialising in the measurement of a group of enzymes called proteases. Increased levels of two of this group of enzymes, thrombin and factor-Xa, has been linked to the fact that some people may have an increased chance of developing blood clots. These blood clots can lead to severe health problems including strokes or organ failure. Pharmaceutical companies who are producing COVID-19 vaccines or developing new drugs to treat COVID-19 patients therefore need to find a reliable method of measuring these proteases so that "at risk" patients can be identified early and treated appropriately. In this project, ProAxsis will use its long-standing and unique expertise in the chemistry of proteases and _in vitro_ diagnostic development to create a brand new combination laboratory test. This test will measure the two key protease biomarkers, thrombin and factor-Xa, at the same time in a clinical sample, using an automated procedure known as multiplexing. ProAxsis has the team in place, and the extensive experience required, to very rapidly create and then up-scale a combination multiplex test for these highly important protease targets. Aside from providing key insights as to why certain vaccines may lead to increased rates of blood clots, this project offers substantial benefits to the patients affected by the COVID-19 virus, the healthcare professional teams providing them with clinical care, and the pharmaceutical companies developing new or repurposed drugs for treating the virus. In turn, this will support healthcare systems such as the UK's National Health Service (NHS) to decide which vaccines and drugs they should prioritise to purchase from their limited budgets, and identify which patients are most likely to respond to the new range of drugs expected to be available. This project specifically focuses on addressing the needs associated with COVID-19 vaccination and treatment, but in the future, this newly developed test could also benefit the large number of people with other conditions caused by increased blood clotting, such as strokes and heart attacks.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: BLOOD;INFECTION
Title: An investigation of the molecular pathology and clinical heterogeneity of theinteractions of haemoglobin E and beta thalassemia, and the relationship of haemoglobin E to malaria, in Asia.
Funder: Wellcome Trust

Abstract: The interaction of haemoglobin E and ß thalassaemia will produce a major public health problem in Southeast Asia in the future as other (non-hereditary) causes of early infant mortality are brought under control. The aims of this programme are, by studying the natural history, pathophysiology and geographic distribution of these diseases, to evolve a strategy for their control in high frequency countries, and to investigate whether (and if so how) they provide protection against P. falciparum malaria. This will enable us to follow up our recent and unexpected observations that protection against P. falciparum by a thalassaemia may be mediated by early exposure to P. vivax, and, moreover, that protection appears to extend to other infectious diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;INFECTION
Title: The health consequences of inherited red blood cell disorders in Kenya.
Funder: Wellcome Trust

Abstract: I will investigate the mechanisms and interactions between a range of human-genetic malaria-protective polymorphisms including HbS, alpha-thalassaemia and G6PD deficiency through both laboratory-based and clinico-epidemiological approaches. Specifically, I will measure the impact of these polymorphisms, both individually and in combination, on well-characterised malaria, and non-malaria phenotypes through laboratory studies and through the analysis of epidemiological data from (i) a birth cohort study of 16,000 children and (ii) a study derived from the continuous surveillance of more than 90,000 paediatric admissions to Kilifi District Hospital in the last 20 years.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;INFECTION
Title: Epistasis and the genetics of disease resistance
Funder: Wellcome Trust

Abstract: A host of genetic blood disorders (such as sickle cell anaemia) are found in malarious regions because they protect their carriers against malaria. However, different populations display different collections of these blood disorders, despite the fact that some are much more protective than others. I have already shown that interactions between a group of disorders called the thalassaemias could be keeping sickle cell out of most of the Mediterranean region. In the present proposal, I intend to use mathematical models to see whether similar processes could explain the patterns seen in Asian and Middle Eastern populations. I will also analyse detailed spatial data from Kenya to look for new inter-gene interactions. There are some combinations of genetic blood disorders about which we know very little; I hope to conduct laboratory studies to learn whether or not they offer malaria protection. The second part of my proposal focuses on interactions amongst the genes of the human immun e system. Two particular sets of genes: the KIRs and the HLAs are organised into distinctive patterns within the genome. I hope to use mathematical models to show whether interactions between KIR and HLA loci, pathogen mediated or otherwise, could be responsible for this organisation.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;INFECTION
Title: Population structure and pathogenicity of C. neoformans in Vietnam.
Funder: Wellcome Trust

Abstract: Cryptococcal meningitis (CM) is caused by a yeast, C. neoformans, which normally lives on trees. Not all strains cause disease - those that can probably do so because they have developed qualities that give them an advantage in a particular environment. These accidently enable them to cause infection. Drugs for CM were invented in the 1950s. New treatments are urgently needed. Yeasts are complex. Their ability to cause disease is the result of many interacting factors. Some have extra genes, o thers have identical genes but express them differently. We want to better understand how C. neoformans causes disease. We have found closely related types that differ in their ability to cause infections. In particular, one affects people with normal immune systems, suggesting it has enhanced ability. We want to find where this type lives in the environment, and to compare how it uses its genetic material to cause disease with closely related strains that are less able. We will use an animal mo del of meningitis, and then test the validity of the findings in human disease by measuring yeast gene expression in cerebrospinal fluid from patients. We hope this will eventually enable the identification of new drug targets.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: BLOOD;INFECTION
Title: Understanding cell fate decisions in normal and abnormal haematopoiesis
Funder: Medical Research Council

Abstract: The research in the Jacobsen laboratory will remain focussed at obtaining a better understanding of the cellular pathways of normal lineage commitment from multipotent HSCs to lineage-restricted progenitors. However, in the coming years, while devoting an increasing emphasis on unravelling the molecular determinants of the now established lineage commitment steps in the earliest stages of lympho-myelopoiesis in adult haematopoiesis, an increasing effort will be devoted towards identifying and characterising the earliest stages of lineage commitment in the embryo. Furthermore, with an increasing understanding of lineage commitment steps in normal haematopoiesis, the Jacobsen laboratory will with support of the strong mouse genetics efforts within the MHU, embark on new research lines, in which the goal is to understand the impact of distinct pre-leukaemic and leukaemic mutations on distinct stages of lineage commitment. Finally, the laboratory will continue their efforts to uncover the cellular and molecular determinants of the haematopoietic defects in MDS, and its transformation to AML.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;INFLAMMATORY AND IMMUNE SYSTEM
Title: Cellular mechanisms of haematopoietic lineage commitment
Funder: Medical Research Council

Abstract: Haematopoiesis has served as a valuable paradigm for how multipotent stem cells are maintained and their differentiation regulated. Thus far elucidation of haematopoietic stem cells and their differentiation, as well as analysis of the alterations they undergo during aging, has generally been hypothesis-driven, enabled by the prospective isolation of discrete cell populations and their functional characterisation. However, recent progress has demonstrated a high degree of complexity of both the haematopoietic stem cell compartment and the pathways by which they form their differentiated progeny, indicating that the current models for how haematopoietic lineage separation are incomplete. With the advent of single cell transcriptome analysis we now have the opportunity to interrogate stem- and progenitor cell populations in a non-biased manner in order to define progenitor populations and their relationships. By combining this technology with novel reporter lines allowing identification of novel stem- and progenitor cell subsets, as well as sensitive readout of erythroid cells and platelets, and the use of lineage tracing, we are now in a position to comprehensively analyse, at the single cell level, the transcriptomes, lineage potentials and cellular relationships within the haematopoietic stem- and progenitor cell compartments. Such studies will allow us to address with a much higher degree of accuracy the impact of aging and oncogenic mutations on the haematopoietic system, and increase our understanding of how immune cell output is modulated by cytokines during microbial insult.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD;INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of platelets in the innate inflammatory response to TB.
Funder: Medical Research Council

Abstract: In tuberculosis (TB) innate immune inflammation leads to tissue destruction mediated by enzymes, particularly Matrix Metalloproteinases (MMPs). Better understanding of TB immunopathology will help identify novel host-directed therapies required in the era of increasing drug resistance. Platelets are immune regulators implicated in many inflammatory diseases, yet little is known about their role in TB. My preliminary data show that activated platelets increase monocyte MMP gene expression, secretion, and functional activity in TB. In patients, secretion of platelet factors (PF4, PDGF-BB, PTX3, and RANTES) are increased at baseline in cases compared to controls and decrease with treatment. These data support the hypothesis that platelets are key regulators of the innate inflammatory response and drive immunopathology in TB. My specific aims are to investigate: 1. Effects of platelets on monocyte differentiation and function in TB. I shall isolate cells from whole blood and measure secretion of inflammatory markers including cytokines and MMPs by Luminex assay and gene expression by qPCR. I will focus on the role of direct cell contact versus indirect signalling through mediators, particularly CD40L. 2. The clinical importance of platelet activation will be investigated in TB patients before, during, and after anti-mycobacterial treatment. Clinical data, sputum culture, and blood samples will be analysed from 120 TB-infected adult patients and 120 controls. Spirometry and chest X-ray will be performed to assess lung damage in TB patients versus controls. Whole blood will undergo FACS for evidence of platelet activity and plasma will be stored at -70C for analysis of CD40L and other inflammatory markers by Luminex. Samples will also be collected from patients undergoing bronchoscopy for analysis of platelet function, collagenase activity by FACS, and disease mechanisms. In summary, his project will define the role of platelets in innate inflammation in TB.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;INFLAMMATORY AND IMMUNE SYSTEM
Title: ANCA vasculitis: -omics to optics
Funder: Medical Research Council

Abstract: Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is a rare, inflammatory disorder with life-threatening manifestations such as rapidly progressive glomerulonephritis and pulmonary haemorrhage. Diagnosis is often delayed and despite treatment, survival remains poor. Early diagnosis and assessing treatment response remain important clinical challenges. I aim to address these challenges by developing circulating microRNA (miR) as biomarkers of vasculitis disease activity and using Optical Coherence Tomography (OCT) to non-invasively assess the microvasculature in patients with ANCA vasculitis Key strengths include: 1. I have support from world-leading expertise in clinical studies. 2. My pilot data demonstrate that the endothelial-enriched miR-126 and chorioretinal thickness report treatment response in ANCA vasculitis. 3. I will recruit patients with ANCA vasculitis from two large, dedicated vasculitis services in Scotland. 4. Data-linkage to ensure comprehensive follow-up of patient outcomes to correlate with my biomarkers. I hypothesise that circulating miR and OCT metrics of microvascular structure will report disease activity in patients with ANCA vasculitis.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: BLOOD;INFLAMMATORY AND IMMUNE SYSTEM
Title: The thymus stromal compartment across developmental stages: Determining single cell transcription, chromatin accessibility and spatial position
Funder: Medical Research Council

Abstract: This research proposal will describe the transcriptional profile, chromatin accessibility and spatial position of all non-haematopoietic human thymus stromal cells analysing tissue isolated at 10-14 and 16-20 weeks of gestation, within the first 6 months of postnatal life and from individuals 20 and 40 years of age. Two distinct single-cell RNA-sequencing approaches will be employed: (i) a microfluidic-droplet-based and (ii) a fluorescent activated cell sorting (FACS)-based method to identify cell states and spaces. The microfluidic droplet-based 3'-end counting method (GemCode Single-Cell Instrument, 10x Genomics, combined with the GemCode Single-Cell 3' Gel Bead and Library V2 Kit) will be used to enable the survey of thousands of stromal cells (notably at relatively lower coverage) and additionally allows to determine both number and relative abundance of individual stromal cell types. Full-length transcript analysis based on FACS-index sorted thymus epithelial cells (TEC; EpCAM+MHC+CD45-) placed into 384 well plates will be employed to allow for a high sensitivity and deep coverage characterization. Standard methods will be employed for the generation of cDNA and library preparation and pooled libraries will be analysed by next generation sequencing. Chromatin accessibility at single cell resolution will be analysed for specific TEC subpopulations using the Chromium ATAC-Seq platform. This data will be used to link regulatory elements to their target genes. Finally, single thymus stromal cells will also be analysed for their spatial position within the complex thymus microenvironment using sequential image captures of immunohistological analyses of in total as many as 52 separate epitopes using a standard, 3-color fluorescence microscope platform. The proposed analyses will define the distribution of distinct thymus stromal cells within the organ and identify non-random spatial interactions in its microenvironment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;INFLAMMATORY AND IMMUNE SYSTEM
Title: Exploring bias in platelet P2Y1 receptor signalling: host defence versus haemostasis.
Funder: Medical Research Council

Abstract: The activation of platelets during inflammation affects their adhesive properties, motility, the release of soluble anti-pathogen factors and their communication with other immune cells to coordinate the innate immune response to infection, or inappropriately in inflammatory disorders, for example asthma and COPD. These functions are distinct to platelet function during haemostasis. Similar activities in leukocytes are controlled by signalling molecules of the Rho family GTPases (RhoA, Rac1), which can be activated by purinergic (P2Y) receptors. Platelets express P2Y1, the role of which in platelet aggregation and haemostasis is well established, yet we have shown that the activation of P2Y1, signalling via RhoA and Rac1 in platelets is required for platelet-dependent neutrophil recruitment, and other platelet functions pertinent to inflammation - however this signalling pathway is ultimately redundant in platelet activation during aggregation. It therefore appears that functional selectivity can occur with platelet P2Y1, dependent on the local tissue environment, to dictate platelet responses (function). The incidence of biased agonism for P2Y1 is novel, but has been described elsewhere for related GPCRS. To understand how platelet P2Y1 might act in a selective manner, we will synthesize novel agonists and antagonists as experimental tools for the orthosteric binding site at P2Y1, and evaluate their potential to influence biased signalling (whether they confer a positive, negative or neutral bias to inhibiting platelet function in the context of inflammation, host defence, and haemostasis) using particular in vitro and in vivo assays to predict platelet activity in the context of respiratory inflammation and infection compared to haemostasis (aggregation, and thromboemboli). This will determine the suitability of targeting platelet P2Y1 as a novel therapeutic area to modulate the inflammatory response.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;INFLAMMATORY AND IMMUNE SYSTEM
Title: Haemoglobinopathies as a target for Fetal Transplantation
Funder: Medical Research Council

Abstract: Background: Models for fetal transplantation are well established, however long-term engraftment of a haematopoeitic stem cell (HSC) allograft has yet to be demonstrated. The mouse model for fetal transplant has closer similarity to human immune development than many published larger animal models (e.g. sheep.) We aim to study allogeneic HSC engraftment in wild type mice and a mouse model of thalassaemia. While whole bone marrow transplantation is able to deliver both engraftment and tolerance, our preliminary data demonstrates that pure HSC are not - suggesting a further cell type is critical in establishing therapeutic effect. Objectives: We plan to identify the tolerogenic cell type within the lineage depleted portion of the bone marrow and deliver this with HSC to fetal mice, demonstrating engraftment levels similar to whole bone marrow. We will then deliver this regimen to a mouse model of thalassaemia. Methods: I will employ a well-studied method of intravascular injection of cells and, using fetal and postnatal endpoints, examine the passage of transplanted cells within the host, as well as study donor-specific tolerance and long-term engraftment of the transplant. Having identified a tolerogenic cell population, I will then deliver a co-transplant of HSC and tolerogenic cells to treat a humanised mouse model of thalassaemia. We will assess the efficacy of this treatment by studying chimerism of haemoglobin in the recipient mice and examining effects on composition of organs such as the heart, liver and spleen. Opportunities of this study: This model for phenotypic correction would be applicable to other haemoglobinopathies (e.g. Sickle Cell Disease) and enzyme storage disease (e.g. Mucopolysaccharidosis); some of these conditions, although rare, pose a significant challenge to the clinician as often a degree of antenatal injury will occur as a result of the defect - as such, the benefits of a successful fetal transplant may be even more measurable.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: BLOOD;INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE