NIHRDataInsights/HRCSData huggingface dataset:
Award Title: UK:Brazil Joint Centre Partnership in leishmaniasis
Funder: Medical Research Council

Abstract: Leishmaniasis is a devastating parasitic disease that targets the poorest of society and is the 9th largest global infectious disease burden (WHO). It is truly a Neglected Infectious Disease as the combined financial support of basic and clinical research equates to <2% of infectious disease R&D resources available. Consequently, there are no vaccines available currently and the limited available treatments are repurposed from other applications, have severe side effects; including anaphylaxis, growing drug resistances and are inappropriate for the primarily juvenile leishmaniasis patients. Disease pathologies range from tegumental (mucocutaneous and cutaneous leishmaniasis) to visceral and cases in Brazil alone range from 20,000 TL to 3,500 VL per annum. The JCPiL will fund five inter-related projects and 3 workshops to promote research at the interface of basic and clinical science, to extend existing collaborations between UK and Brazil and to develop new partnerships and interdisciplinary ways of working. Travel will be used to cross train PIs, PDRAs and PhD students in the foremost technologies and expertise available worldwide. Studies will be focused on understanding parasite genetic diversity in the context of variations of Leishmania infectivity and virulence factor expression, mechanisms of immune evasion, diversity of host response, resultant immunopathology and sustained activation that drives chronic disease. We will investigate novel molecular targets of vulnerable pathways that are essential to Leishmania viability, optimise techniques and diagnostic markers to predict and definitively categorize patient pathology profiles to inform more bespoke, effective treatment design. Our JCPiL will create new collaborations in order to build sustainable, fundable future projects and make an impact on this deadly disease.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: UKPRP Community of Practice
Funder: Medical Research Council

Abstract: Five Development Themes will launch at the outset of the CoP.   1. UKPRP Networks Aim: to develop the Network's capabilities by exchanging knowledge and developing best practice, and to explore solutions to common network issues (e.g. building cross-sector research capacity). Outputs: to include best practice guidelines, case studies, and identification of potential projects for Networks to progress based on initial discussion around shared priorities.   2. Consortium and Network Management Aim: to share learning around the formation, implementation and operation of effective multi-sector collaborative groups. Outputs: to include a toolkit for and guidance on the management of large-scale collaborative projects, including evaluation.   3. Impact-Oriented Research Aim: to co-develop a shared understanding of approaches to impact-oriented prevention research, and to critically assess different approaches to impact. Outputs: to include an impact report comparing approaches across the Networks and Consortia and an understanding of how the DT has helped strengthen impact strategies.   4. Commercial Sector Interactions Aim: to share, compare and reflect on Network and Consortia approaches to managing interactions with and interference by commercial sector organisations. Outputs: to include guidance on issues and approaches for the management of commercial interactions, and/or attempted interference with the conduct or impact of prevention research.   5. Meta-Research Aim: to collect, review and evaluate the approaches UKPRP projects are taking to reflect on and continually improve their research, stakeholder engagement, knowledge exchange and impact realisation processes and practices, and to seek to enhance the outcomes of our research by sharing know-how across the portfolio of participating UKPRP projects. Outputs: to include a 'playbook' as a knowledge base for future researchers and research funders to use when developing research calls and bids.


Research Activity Codes: 3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: UKRMP Hub: The Engineered Cell Environment.
Funder: Medical Research Council

Abstract: The UKRMP Engineered Cell Environment Hub (ECEH) aims create a platform, linking excellence in the regenerative biology of the stem cell niche with experimental medicine to translate regenerative therapies to the clinic. We will bring together leading scientists in regenerative biology, stem cells, niche biology, phenotypic screening, safety and transplant immunity with clinician scientists working in regenerative medicine in a highly collaborative network.  We will develop two linked translational regenerative strategies: (1) Developing Cell Therapies for Damaged Organs: We will use our knowledge of niche biology to optimise cells for therapy. Artificial niches will be constructed that mimic healthy tissue and facilitate effective cell therapy. Pluripotent and adult human stem cell sources will be optimised in vitro and tested in our pre-clinical models of liver, joint and lung repair. Immune responses to the transplanted cells will be assayed in relevant humanized mouse models. (2) Promoting endogenous repair of damaged organs:Using stem cells in vitro, we will create high content 2D and 3D phenotypic screens for liver, cartilage and lung repair. We will study the behaviour of stem cells in their niche aiming towards optimising endogenous repair and use FDA approved compound libraries to identify potential drugs and biological agents for translation. The Hub is structured with 3 basic underpinning scientific areas and technologies: (a) Understanding and improving the physical properties of Aged and Injured Tissue Niches; (b) Developing Artificial Wnt Niches to act as regenerative signals for tissue formation and repair; (C) High content phenotypic screening for the discovery of novel targets for endogenous repair.  We have 3 clinical translational exemplars: liver (WP1), joint (WP2), lung (WP3) repair. Each theme is led by a pair of investigators with complimentary expertise, common underpinning biology and enabling technologies that span the WPs.


Research Activity Codes: 5.2 CELLULAR AND GENE THERAPIES
Health Categories: ORAL AND GASTROINTESTINAL;MUSCULOSKELETAL;RESPIRATORY
Award Title: Understanding Chemotaxis Towards Self-Generated Gradients Using Computational Models, Model Organisms and T cells
Funder: Wellcome Trust

Abstract: Cell migration is essential to processes throughout biology, especially embryonic development and immune function. Migration must be steered to be physiologically effective. Steering cues are not well understood; we know a lot about how cells interpret them, but relatively little about how they are generated.
The basic premise of this work is that the cells often generate their own cues, by breaking down attractants that are widely present (and thus initially give no steering information) into local gradients. Attractant breakdown and migration happen simultaneously. This mechanism - chemotaxis up self-generated gradients (SGGs) - is hard to dissect because it is complex, and based on positive feedback loops. We therefore propose a four-pronged, iterative approach, in which we combine less challenging components to create an understanding of the underlying biology.
Key goals are:
(1) explore possible mechanisms and new extensions using computational models;
(2) test outcomes using chemotactic Dictyostelium in custom microfluidic devices;
(3) verify these data by establishing cultured T cells chemotaxing to CCL19 as a model SGG;
(4) combine findings from parts 1-3 to make a 3D, SGG-based model of a lymph node.
Together they will illuminate chemotactic steering in general, by focussing on one physiologically important system.

Lay Abstract: When immune cells find disease in the body, they take evidence to a centre of operations called a lymph node. Many different cells of the immune system need to communicate there. They therefore need an effective way of navigating to the lymph node, and finding one another after they arrive.
 
We have shown that this navigation is an active process - cells create a pathway by changing their environment. The way they do this is complex, and almost impossible to study with simple experiments. We deal with this complexity by combining different simpler experiments - computer models let us explore a range of possible conditions; amoebas are good navigators and easy to study; and single isolated immune cells. Ultimately, we will make a functioning 3D model of a lymph node, to show exactly how different kinds of immune cell navigate around it in order to find each other.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Understanding Tobacco Industry Pricing, Profits, and Taxation in Low and Middle-Income Countries
Funder: Cancer Research UK

Abstract: Tobacco tax increases are the most effective way of reducing tobacco use and addressing the inequalities inherent to tobacco use.  Past research has found that the Tobacco Industry (TI) uses its pricing strategies to undermine the impacts of tobacco taxes in high income countries such as the UK.  What isn’t currently known is if the TI also uses the same tactics in Low and Middle Income Countries (LMIC), whether they are adjusted for local market conditions, and what other strategies are used in such settings in order to maintain or enhance industry profitability. Similarly, little is known about tobacco industry profitability in these countries, or the accuracy of industry reporting on this issue.   The goal of this PhD to understand how the industry prices and profits from its products in a variety of LMIC, and hence how policy makers should appropriately respond to address the actions of tobacco companies that are increasingly focusing on LMIC.


Research Activity Codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health Categories: CANCER AND NEOPLASMS;CARDIOVASCULAR;RESPIRATORY;STROKE
Award Title: Understanding actin-dependent chromosome cohesion in mammalian eggs
Funder: Wellcome Trust

Abstract: Every human life starts when an egg is fertilised by a sperm. For poorly understood reasons, eggs frequently contain an incorrect number of chromosomes. This chromosomal abnormality is a leading cause of embryo deaths in humans – it accounts for nearly 35% of miscarriages. Chromosomal abnormality in embryos also leads to genetic disorders such as Down’s syndrome, which affects about 1 in 1,000 live births worldwide. My PhD project is aimed at understanding which cellular processes protect eggs from having an incorrect number of chromosomes before fertilisation. In this regard, I will investigate a recently discovered and unexpected function of the actin cytoskeleton in preventing chromosomal abnormality in eggs. In the future, knowledge obtained from my research project could be exploited to improve the outcomes of fertility treatments as well as prevent pregnancy loss.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Award Title: Understanding and exploiting Group A streptococcal anti-chemotactic proteases in vaccines for infection
Funder: Wellcome Trust

Abstract: Streptococcus pyogenes is a major human pathogen responsible for a significant global disease burden.  Despite a century of research, there is no effective vaccine, in part due to the existence of multiple serotypes that vary worldwide. Notably, S. pyogenes produces two surface-associated serine proteases that inactivate specific neutrophil chemotactic signalling families. SpyCEP cleaves and inactivates the entire family of neutrophil-active CXC-chemokines including IL8/CXCL8, while C5a peptidase (ScpA) cleaves and inactivates both C5a and C3a.   Both SpyCEP and ScpA are major, yet fully conserved, targets in the protective human antibody response against S. pyogenes and are therefore leading candidate vaccine targets. There is, however, minimal structural information to indicate how these proteases function to recognise or cleave their substrates, nor factors that influence activity.   We will undertake     • Comprehensive evaluation of the structures of each enzyme complexed with substrate   • Detailed examination of enzymology and substrate specificity   • Systematic study of the expression and role of the enzymes in vivo   • Use the above data to develop and design hybrid vaccine antigens to evaluate in vivo       Such information would greatly advance our fundamental understanding about this family of enzymes, providing a platform for novel vaccine antigen design, and future opportunities for drug development.

Lay Abstract: Group A Streptococcus – also known as Strep A- causes over half a million deaths annually, by triggering rheumatic heart disease in children with repeated minor streptococcal infections, and also by causing more lethal infections and sepsis. These could all be prevented if there was a vaccine active against all types of Strep A.  Two enzymes made by Strep A are known to fight the immune response by cutting immune system chemical messengers in two. Understanding how the enzymes work could help design better drugs to fight unwanted inflammation in the future.   Most importantly, we know that these enzymes can be used as vaccines against Strep A, but do not understand their structure. In this project we will work out how these two enzymes interact with the chemical messengers, and work out how to adapt the enzymes’ structures to make the best possible vaccine against Group A Streptococcus.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: Understanding and learning from the impact of changes in colorectal cancer care delivery in light of COVID-19 and their interplay with socioeconomic inequalities
Funder: The Health Foundation

Abstract: The COVID-19 pandemic has resulted in rapid changes to health service delivery, with important implications for cancer care. These changes influence the way in which someone can contact their GP, how people are tested for cancer, how teams come together to determine the best treatment plan, and what type of treatment is offered.

Some of these changes will be advantageous to patients (for example, more flexibility), but there are also challenges, and some changes may be beneficial for some and not others. For example, being able to access health care remotely requires a smartphone or a computer, which many do not possess or cannot fully use.

Another important consideration is that people from more deprived areas of the UK have worse cancer outcomes than people in less deprived areas (the deprivation gap). There is concern that the rapid changes in care during COVID-19 could have increased the deprivation gap in cancer care.

This research project will use colorectal cancer as an exemplar to help understand the impact of changes in cancer care on patient experience and outcomes.

The project team will hold interviews with patients from high and low deprivation areas of the UK who have contacted their GP with a concerning symptom during the pandemic, and with health professionals in community and hospital settings.

This evidence, combined with information from national guidance documents, will be used to develop recommendations on optimal practice to manage care and protect patients in the context of similar pandemics.


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: CANCER AND NEOPLASMS
Award Title: Understanding evolutionary constraints in sporadic and inherited renal cell cancers
Funder: Cancer Research UK

Abstract: Background

In the interim analysis of the TRACERx Renal study (Tx100) (1, 2), we detected conserved patterns of mutation ordering, co-occurrence and mutual exclusivity, and repeat parallel evolution, in primary tumours, while route to metastases converged on a common genomic solution, copy number alterations. These findings illustrate that cancer evolution is highly constrained by selection. However, the impact of mutation supply, tumour microenvironment (TME) and therapeutic intervention on the opportunity and strength of selection is unknown. ccRCC is an excellent model to explore these questions. 

Aims

1.	Resolving clonal dynamics
2.	Understanding the fitness landscape
3.	Investigating evolution of von Hippel Lindau Disease
4.	Evaluating clonal dynamics through representative sequencing

Methods

1. micro-clonal dynamics will be resolved through a mini-bulk sequencing approach 
2. the role of TME will be evaluated through immuno-histochemistry and RNA sequencing 
3. the evolution of VHL disease will be analysed through bulk DNA sequencing and immunohistochemistry
4. representative sequencing will be performed on homogenised surgical to derive pervasive patterns of clonal evolution.

Outputs

This programme will derive a fitness landscape map that reveals the most critical steps in tumour evolution, especially triggers of progression, and provide a standardised approach to understanding clonal dynamics and their impact on clinical phenotypes.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Understanding individual differences in facial emotion perception and their association with psychiatric risk indicators
Funder: Medical Research Council

Abstract: The aim of this project is to understand why atypical processing of emotional facial expressions is associated with many clinical disorders. Although it is well established that atypical processing is associated with increased psychiatric risk, the cognitive basis of atypical processing is not known, and this has prevented progress in diagnosis and treatment. Knowing why some people show atypical processing requires knowing what emotional expressions look like to different people, but technical limitations have previously made it impossible to establish what an emotional expression looks like to an individual. We have now overcome this limitation by combining ground breaking computer graphics techniques and state-of-the-art behavioural methods. The new tools use genetic algorithms that allow individuals to create the facial expressions that they associate with particular emotions. In each iteration of the algorithm, selected characteristics are bred to create a new 'generation' of facial expressions. The process is repeated until convergent on an expression associated with a particular emotion ('happy', 'sad', 'angry').  We propose to use these 'evolved' faces to gain knowledge about emotion expression recognition in typical and high trait populations, thereby improving clinical and pre-clinical studies of emotional processing. We will use the new tools to allow participants to create their own facial expressions. We will then use machine-learning techniques to quantify and characterise the facial configurations created by typical and by individuals with high trait anxiety or psychopathy. We will use these evolved expressions to establish the role of perceptual differences in atypical emotional processing in high trait groups, by using them in conventional clinical and pre-clinical emotional tests instead of standard faces. We will ensure maximum uptake of our toolkit by making it open access, and easy to use.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: MENTAL HEALTH
Award Title: Understanding mechanisms that drive pain perception in early human development
Funder: Wellcome Trust

Abstract: Pain in infancy has negative long-term consequences and its prevention is a clinical priority, but adequate treatment requires mechanistic understanding of the structural and functional development of human nociceptive circuitry. Recent scientific and technological advances provide insights into how noxious information is transmitted to the infant brain, providing a platform to ask how intrinsic brain network connectivity and the environment affect noxious-evoked brain activity, behaviour and ultimately pain perception in the developing infant nervous system. The fellowship goal is to understand the mechanisms that drive and modulate pain perception in early human development. I will ask whether inherent differences in how the brain behaves at rest influence variability in noxious-evoked activity, and will determine how this relationship is altered by environmental factors and pathology. I will establish how the development of structural and functional network connectivity alters noxious-evoked brain activity, and influences the dynamic relationship between brain activity and behaviour. I will translate this mechanistic understanding into clinical practice by conducting a clinical trial of an analgesic (fentanyl) during a minor surgical procedure, and will establish whether our newly-developed measures of noxious-evoked brain activity are suitable for use in infant analgesic dose-finding studies.

Lay Abstract: Thirty years ago, it was commonly believed that infants do not feel pain. Surgeries were carried out without adequate pain relief, based on the misconception that the infant nervous system is too immature to process pain and on concerns about side-effects of pain relieving drugs. Happily, this has changed, and infants now routinely receive pain-relief during surgery. However, there is still an acceptance that medical procedures – such as taking blood samples, vaccinations, or tongue-tie division – will be performed without pain medication. For a hospitalised infant, medical procedures are an everyday occurence, and the youngest and sickest infants may experience more than 50 painful procedures per day.
 
 
 
Given the negative consequences associated with early life pain, which include long-term changes in brain development that are linked to reduced academic performance in school-aged children, improving pain treatment in infants is central to our responsibility to protect children in our care. However, as infants cannot describe their pain, we are reliant on alternative methods to measure pain experience. The fellowship goal is to understand how brain development leads to pain perception; to investigate the consequences of early life pain on brain development; and to develop new pain treatment options for infants.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: MENTAL HEALTH;NEUROLOGICAL