NIHRDataInsights/HRCSData huggingface dataset:
Title: Magnetic Nanotechnology to Treat Venous Thromboembolism
Funder: Wellcome Trust

Abstract: Current front-line venous thromboembolism (VTE) treatments involve the systemic administration of anticoagulants to control thrombus growth and/or the application of thrombolytic enzymes to try to lyse the clot, although both exert a systemic effect in the patient body, potentially leading to major bleeding. Iron oxide nanoparticles (IONPs) have been used to generate targeted hyperthermic responses to destroy pathological structures (magnetic hyperthermia - MH). Here size-controlled IONPs will be synthesised and multi-functionalised (mf-IONPs) with anti-fibrin IgG antibody and tissue plasminogen activator (tPa) through covalent bonding onto the IONPs surface using click-chemistry techniques. These mf-IONPs will target venous thrombi and in-situ magnetic stimulation will produce a localised hyperthermic stimuli to trigger the apoptosis/necrosis of thrombi-lodged erythrocytes and platelets, whilst also improving the action of the temperature sensitive tPa, therefore reducing the secondary effects associated with traditional therapies. Our study intends to demonstrate the clinical potential of this nanotechnological-based VTE therapy by using a tissue-engineered vein model that mimics the fluid shear conditions of human blood vessels. This model, together with limited in-vivo studies, will confirm the biocompatibility of this technique. The outcomes of this study will allow to endeavour further steps to pave the way for translation into the clinic.

Lay abstract: Current pharmacological venous thrombosis (VT) treatments act on the whole body, leading to important secondary effects such as major bleeding in some patients. I aim to develop an effective, localised-action VT therapy that avoids the above-mentioned secondary effects, by using biocompatible iron oxide nanoparticles (IONPs) labelled with clot disrupting enzymes and antibodies to target venous blood clots. IONPs will be stimulated with magnetic fields to locally increase the temperature of the clot, destroying its cells and boosting the temperature-dependant action of the enzymatic drug with minimal effect on the vein tissues. To assess the functionality of this therapy and significantly reduce the need of animal experiments in my research, I will fabricate a tissue-engineered vein system that will mimics the human vein conditions. These studies will allow to assess the feasibility of using nanotechnology to treat VT in more efficient and safe manner that traditional systemic drugs.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;CARDIOVASCULAR;CANCER AND NEOPLASMS
Title: Fibrin at the interface of platelet activation and thrombus stabilisation
Funder: Wellcome Trust

Abstract: We have recently shown that fibrin, but not its precursor fibrinogen, activates platelets through a receptor complex, GPVI-FcRg-chain, which was identified by one of us (SPW) in the 1990s, and is recognised as the primary signalling receptor for collagen. The paradigm-changing observation that GPVI is a receptor for fibrin establishes a role for GPVI not only in initiation (via collagen) but also in propagation (via fibrin) of thrombus growth and may explain the increase in embolisation in thrombosis models in GPVI-deficient mice. We propose that the interaction of fibrin with GPVI represents a target for a new class of antiplatelet agent that may have benefits over current antiplatelet drugs. To investigate this we will map the site of interaction of fibrin with GPVI and develop agents (inhibitors and mouse models) that block this interaction but preserve the activation of GPVI by collagen. We will use these to determine the importance of GPVI-fibrin in haemostasis and thrombosis, and in other vascular pathways where GPVI is known to play a role including maintenance of vascular integrity.

Lay abstract: We have recently shown that fibrin, but not its precursor fibrinogen, activates platelets through a receptor complex, GPVI-FcRg-chain, which was identified by one of us (SPW) in the 1990s, and is recognised as the primary signalling receptor for collagen. The paradigm-changing observation that GPVI is a receptor for fibrin establishes a role for GPVI not only in initiation (via collagen) but also in propagation (via fibrin) of thrombus growth and may explain the increase in embolisation in thrombosis models in GPVI-deficient mice. We propose that the interaction of fibrin with GPVI represents a target for a new class of antiplatelet agent that may have benefits over current antiplatelet drugs. To investigate this we will map the site of interaction of fibrin with GPVI and develop agents (inhibitors and mouse models) that block this interaction but preserve the activation of GPVI by collagen. We will use these to determine the importance of GPVI-fibrin in haemostasis and thrombosis, and in other vascular pathways where GPVI is known to play a role including maintenance of vascular integrity.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD;CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Non-invasive biomarkers of stress in mothers, fathers and infants in urban and rural Malawi: a feasibility study
Funder: Medical Research Council

Abstract: Two recently funded major population research studies on chronic conditions in Malawi will include the capacity to monitor a family's physical and mental health during the mother's pregnancy and the subsequent health of her infants. Malawian infants are growing up in one of the least developed countries in the world and are at high risk of infections in childhood and cardiometabolic disease in young adulthood. In this seed-funding application we wish to determine the feasibility and acceptability of collecting non-invasive biological samples for measurement of 'stress' hormones (glucocorticoids) from mothers, their partners, and their infants. These include hair, breast milk as well as self-collected saliva samples, collected at home. We will explore both participants' and staff views of collecting the samples, assess the quality of samples collected and make any necessary changes to our protocols. The findings will pave the way for a future funding application for a nested study within the larger studies. This will add value to the existing MRC- and Wellcome-funded work through exploration of underlying biological mechanisms linking early life development with later life disease. The proposed seed-funding will also build local capacity and expertise in use of non-invasive biological samples, which we identify to be of wider relevance for other work in Malawi.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD;CARDIOVASCULAR;METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Title: Thrombotic Thrombocytopenic Purpura: A novel assay to monitor disease and prevent relapse
Funder: LifeArc

Abstract: This project aims to improve the treatment of patients who have the rare life-threatening disease Thrombotic Thrombocytopenic Purpura (TTP) – a disease often only diagnosed when patients show symptoms of multiple organ dysfunction caused by multiple small blood clots in the vessels that supply the organs with oxygen. TTP occurs in people with a deficiency of a specific enzyme, ADAMTS13. The enzyme is important in preventing excess bleeding or clotting and its primary role is to keep the level of an important protein in blood clotting under control. Following initial treatment, patients require lifelong monitoring to prevent subsequent episodes. Laboratory tests measure ADAMTS13 activity to both confirm the diagnosis and minimise the risk of subsequent episodes. But anticipating which patients are relapsing when their levels of ADAMTS13 fall from a normal range is difficult to assess as some patients’ levels stay below 10% throughout remission. This makes decisions about the timing of treatment (with the drug rituximab) challenging. In addition, these tests only tell clinicians the level of the enzyme and do not help them understand the underlying impact of the small clots that cause symptoms. The team has developed a new test for TTP patients which mimics high blood flow through a small vessel and provides a comprehensive assessment of the increased small blood clot risk, the cause of organ damage in TTP patients. The aim is to optimise and evaluate this new test in a large number of TTP patient samples so that it provides additional information on the underlying disease and enables personalised patient therapy. Preliminary data shows that it is possible to distinguish the blood of a TTP patient from normal healthy control blood. The test detects increased formation of microthrombi (a microscopic clump of fibrin, platelets, and red blood cells) in TTP patients with normal platelet counts, which explains non-acute symptoms that have previously been overlooked. Ultimately, the team plans to develop the test so it is available on routine coagulation analysers that analyse fresh or stored blood samples and could produce results within half an hour. The team plans to optimise and evaluate the test in a large number of TTP patient samples at different stages of their condition. They will compare the results to current standard ADAMTS13 tests, clinical data and routine laboratory tests. This should improve the new test by making it less labour-intensive and more attractive for regular use in patients. It will provide additional information on the underlying disease pathology to enable personalised patient therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: BLOOD;CARDIOVASCULAR;STROKE
Title: Endothelial Cell Function and Weibel-Palade Bodies.
Funder: Medical Research Council

Abstract: Overall Aim and Importance Weibel-Palade Bodies (WPB) are the cigar-shaped multifunctional secretory granules of endothelial cells. They carry molecules necessary to haemostasis/thrombosis, inflammation, the control of vascular tonicity, and angiogenesis. They are thus of central importance in the endothelial contribution to vascular health and disease. Reduction of the level of their major component, Von Willebrands Factor, cause von Willebrands disease- the commonest inherited human bleeding disorder, but perhaps more importantly, higher levels of VWF are associated with Diabetes, Atherosclerosis, Coronary Artery Disease, Stroke, Deep Vein Thrombosis, Reperfusion Injury, and Pulmonary Embolism. The association of WPB components with this range of globally important diseases justifies significant investment in increasing our understanding of these organelles. We have discovered a set of cellular components that control the formation and exocytosis and thus functioning, of these organelles, and we wish to understand how these controls work together to produce their final functional output. We wish to underpin and exploit a conceptual shift towards a new model where WPB formation and exocytosis are actively modulated. Objectives 1. Determine how changes to WPB size caused by cellular controls produce different functional responses to different endothelial agonists. 2. Determine how different cellular controls act in concert to produce a final functional output from the WPB and thus control the activated endothelial cell phenotype. 3. Identify and characterise new controls on endothelial phenotype that operate through WPB. Plan and methodology Cellular controls so far discovered act to control WPB size; to control WPB maturation (and thus VWF multimerisation); to control WPB exocytosis. We will determine how these three aspects of control operating to modify the final functional output from these organelles combine to affect four key endothelial functions using in vitro assays. Specifically, we will measure the effect of modulating machinery from more than one category on: WPB size and number; maturation and thus multimerisation of VWF; WPB exocytosis. The data from these will then determine which modulations will be tested for their effects on: Recruitment of plasma VWF to the activated cell surface; Recruitment of platelets by activated endothelial cells; Recruitment of leukocytes to the endothelial surface; Extravasation of leukocytes. These functional assays will be carried out in flow experiments, using both simple and more complex chambers.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;GENERIC HEALTH RELEVANCE
Title: New strategies to reduce anaemia and risk of overweight and obesity through complementary feeding of infants and young children in Peru
Funder: Medical Research Council

Abstract: There are three main components (work packages) to the research. Work package 1 will conduct formative research on the drivers of infant and young child feeding patterns and practices in relation to caregiver behaviours and household, community and socio-cultural environments. Qualitative and quantitative methods include i) quantitative dietary intakes of infants assessed through 24hr recall ii) 28-day food frequency questionnaires of mothers/caregivers iii) household observations (feeding style, mealtimes, snacking, food environment) and iv) in-depth interviews with maternal and non-maternal caregivers. We will then examine infant and young child feeding (IYCF) practices in the context of health services and daycare facilities to further understand feeding styles and food consumption patterns and practices. A policy mapping component will critically review policy developments and implementation on IYCF in relation to the Double Duty Actions on over- and under-nutrition. Findings from the formative research will be synthesised to identify the key challenges in adopting healthy complementary feeding practices in the two ecological settings (coastal Lima and highland Huanuco). Work package 2 is a community based participatory design process. Through a series of six sequential workshops with stakeholders and end users (caregivers and families, health professionals, local government) we will formulate the key challenges, then use idea generation and 'futures' workshops to develop prototypes for solutions and interventions to address the dual challenge of micronutrient deficiency and obesity prevention in infants and young children. Work package 3 will pilot the prototype interventions in households, communities or government health facilities. We will conduct qualitative evaluations of the pilot including acceptability, usability and relevance and bring the body of evidence to a reflective workshop involving the investigators, stakeholders and government.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: BLOOD;GENERIC HEALTH RELEVANCE
Title: The role of cell cycle exit in EHT and the haematopoietic niche
Funder: Wellcome Trust

Abstract: Haematopoietic stem cells (HSCs) have been used for the treatment of diseases including immune deficiencies and metabolic disorders, as well as bone marrow repair after radiation treatment. In order to harvest their full potential, it is essential that we expand our understanding of HSC development and function. A vital part of HSC generation in the developing embryo is the transition of a subset of endothelial cells into blood cells. This occurs under the control of a multitude of factors within the cell and those present in the surrounding environment, the hematopoietic niche. The cell cycle has been shown to be an important involved in the cellular differentiation process, as some cells need to exit the cell cycle in order to undergo the transcriptional and morphological changes associated with differentiation. In my project I will investigate the impact of various factors as cell cycle regulators in this early differentiation of endothelial cells into haematopoietic cells. These studies will employ genetically modified mice, alongside state-of-the-art in-vitro and transcriptional profiling techniques such as single-cell RNA-sequencing. We expect our research to help elucidate the origin of HSCs and therefore contribute to our understanding of how to generate these cells in-vitro.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: BLOOD;GENERIC HEALTH RELEVANCE
Title: Cross-interaction of the innate immune response (complement system) with coagulation proteins in blood disorders
Funder: Division for Social Care and Health Research (Wales)

Abstract: Complement is the primary immune defence against bacterial infection, having powerful cell-killing properties. Clotting prevents bacteria from entering through a wound into the blood stream. Both systems are individual blood protein cascades that are tightly regulated to prevent non-specific damage to our own bodies cells/tissue. My research has shown that genetic complement protein variants promote dysregulation, enhancing systemic complement activity, leading to self-tissue damage. Several complement-associated diseases have also shown evidence of uncontrolled clotting. Sepsis (blood poisoning) is a common condition (90,000 UK admissions/year) and the most prominent example of dysregulated complement and clotting activity, leading to multi-organ failure and death (36,000 UK deaths/year). Sepsis is poorly understood because of the complexity of the interactions of complement and clotting. Dissecting the mechanism is crucial for early intervention, key to survival and multi-target therapy development. Complement protein “C3” drives complement killing by depositing “C3b” on cells/tissue. “C3b” can interact with the membrane-bound clotting regulator “thrombomodulin”, which helps decreasing complement activity. “C3” and “thrombomodulin” are biomarkers associated with poor sepsis outcome. I propose that this interaction is key to uncontrolled amplification of complement and clotting in sepsis. Knowledge of the mechanism will aid identify patients with increased susceptibility for early intervention therapy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: BLOOD;INFECTION
Title: Iron, Infection and Anemia
Funder: Medical Research Council

Abstract: Iron deficiency (ID), leading to iron deficiency anemia (IDA) and impaired neurocognitive development, remains the most pervasive nutritional deficiency worldwide. Using currently accepted criteria the prevalence rates for IDA in mothers and young children frequently exceed 50% in low-income countries. Low cost iron supplements are efficacious in combatting IDA but recent large-scale trials have revealed extensive evidence of harm especially (but not only) in malarious areas. It is assumed that all of these adverse outcomes are attributable to host-pathogen competition for iron whereby supplemental iron has favoured pathogens more rapidly than their host; a phenomenon termed the ‘iron trap’. Thus there is an urgent need: a) to understand the pathways by which provision of iron favours pathogen virulence; and b) to use this knowledge to design safer modes for preventative and therapeutic provision of iron to pregnant mothers and their infants living in infectious environments. The discovery of hepcidin, the master regulator of iron metabolism, offers new insights into the host-pathogen battle for iron and we are using this to develop new ways to safely administer iron.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: BLOOD;INFECTION
Title: Identification of specific metabolites in mycolactone producing mycobacteria and Buruli ulcer infection: diagnostic biomarkers through metabolomic
Funder: Medical Research Council

Abstract: Buruli ulcer (BU) is a severe, slow progressing necrotizing skin infection caused by the environmental mycobacterium, Mycobacterium ulcerans. The disease is classified as a neglected tropical disease despite being described in over 30 countries including Ghana, Togo, Benin, Côte d'Ivoire, Cameroon, Mexico, Papua New Guinea, South East Asia and Australia, mostly affecting individuals in rural communities living in endemic areas. BU is characterized by nodule, papule and plaque formation which ultimately develops into large painless ulcers with undermined edges. The WHO's Global BU Initiative has identified the development of simple diagnostic tools as one of the priority areas to control BU. In a pilot study, funded under the Cambridge-Africa Partnership for Research Excellence, we sought to determine the best sample matrix for the identification of metabolites from M. ulcerans that can be found only in BU patients using gas chromatography mass spectrometry based metabolomics. We identified tissue biopsy and fine needle aspirates as the best specimens for the identification of metabolites in preference to lesion swabs. Metabolites identified in both groups of patients included cadaverine and putrescine, associated with degenerating tissue. In this proposal, we are seeking to further this pilot study, building on our observations and collecting the tissue biopsies and fine needle aspirates from a larger patient sample cohort to allow us to perform a more detailed analysis of the metabolome of the host and mycobacterium BU. To gain more insight into the novelty of the biomarkers we identify, we will include another phase of experimentation which involves the characterization of the lipid and aqueous metabolome of M. ulcerans and other mycolactone producing mycobacteria including M. pseudishottsii, M. liflandii and M. marinum DL. This project aims to identify novel biomarkers for disease diagnosis and give insight to the biology of the mycobacterium during infection.


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