NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Inflammatory arthritis - time to reveal the bigger picture
Funder: Versus Arthritis

Abstract: Rheumatoid arthritis (RA) is a debilitating autoimmune disease affecting 1% of the UK population.  One of the defining features is daily rhythmicity in inflammation.   RA patient commonly experience early morning pain and stiffness (even in the advent of biologic treatments) severely impacting quality of life.   Our studies in pre-clinical models recognise that the inflammatory environment within the joint exhibits 24h (circadian) variation, but mechanisms driving this remain to be elucidated.   Additionally, there is an increasing appreciation that RA is associated with changes in the composition of the gut microbiome, although the full impact of this is not yet understood. This microbial community is a critical regulator of immunity which exhibits circadian oscillations in abundance and function.   To date, the vast majority of studies aimed at understanding mechanisms driving inflammatory arthritis do not consider time-of-day, providing only a snapshot.  To see the bigger picture, we must take time-of-day into consideration.  

This proposal defines an integrated programme of research spanning human RA studies and pre-clinical models aimed at establishing mechanistic links between the clock, immunity and microbiome.  The overarching aim is to understand the temporal dependence of mechanisms driving the development, progression and treatment of inflammatory arthritis, with the ultimate goal of identifying novel therapeutic targets.   Clinical studies include analysing the cellular composition and activity of joints at the peak and trough of inflammation.  Furthermore, patient fecal samples and blood samples will be utilised to provide a temporal profile of the gut microbiota and its metabolic outputs in health and disease.  This work package will be supported by pre-clinical models using transgenic mouse lines and microbial manipulations to explore mechanisms driving temporal variation in disease and the microbiome and their consequences.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Information-seeking in health and disease
Funder: Wellcome Trust

Abstract: People spend a substantial amount of time seeking out information (e.g., reading, asking questions, internet browsing). It is theorized that common psychiatric conditions, including depression and anxiety, are characterized by abnormal information-seeking patterns. These patterns could potentially be measured and used to facilitate diagnosis and treatment selection. However, the precise links between information-seeking and psychopathology are unknown. In fact, we know little about how to quantify information-seeking or the mechanisms that control it. 
 
My aim is to understand (i) how people decide to seek or avoid information and (ii) how those decisions relate to mental health. I have developed tasks to quantify key drivers of information-seeking (including valence of information, uncertainty, instrumental utility). I will test participants to assess whether psychopathology symptoms are linked to abnormal influence of these drivers on information-seeking. I will also combine pharmacological manipulation with neuroimaging to examine whether the influence of these drivers is dependent on dopamine – a neuromodulator that malfunctions in several conditions in which information-seeking is theorized to be altered- and identify the neural computations involved. I will assess whether these drivers are over/under expressed in individuals diagnosed with affective disorders, and conduct experiments to determine how these alterations impact well-being.

Lay Abstract: The human pursuit of knowledge drives intellectual development and social engagement. It is theorized that the tendency to seek out information is altered in common psychiatric conditions including depression and anxiety. Because people regularly engage in information-seeking online, there is a constant stream of data that could theoretically be used to facilitate diagnosis and treatment selection. However, the precise links between information-seeking and mental health have not been established. Moreover, we know little about how to quantify information-seeking or the neural mechanisms supporting it.

I aim to fill these gaps. I have developed tasks to quantify distinct drivers of information-seeking across domains of knowledge. I will test participants to assess links between abnormal influence of these drivers and psychopathology symptoms. Further, I will examine whether certain psychotropic drugs alter information-seeking behavior and characterize the underlying neural mechanisms. Additional studies will examine how patterns of information-seeking impact mental health.

Research Activity Codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: MENTAL HEALTH
Award Title: Innate immunity and inflammation in tuberculosis: insights from the zebrafish and therapeutic opportunities
Funder: Wellcome Trust

Abstract: Despite > 60 years of antitubercular chemotherapies, tuberculosis (TB) has been the leading infectious cause of death.  My laboratory pioneered the zebrafish - Mycobacterium marinum tuberculosis model to better understand TB pathogenesis. It enabled surprising discoveries about tuberculosis with immediate implications for new therapeutic modalities. Here, we will use the zebrafish to discover genetic alterations that impact upon immunity and inflammation in early TB. This will uncover human genetic susceptibilities to tuberculosis and druggable pathways underlying them. Our key goals are to: - Map and characterize hypersusceptible zebrafish mutants identified in a forward genetic screen. We will identify their causative lesions and characterize which infection step is altered in them and how, so as to understand how these genes modulate infection. - Identify gene-regulatory networks involved in early granuloma formation. RNA-seq analyses will provide a blueprint of gene expression changes associated with tuberculous granuloma formation, which we will link dynamically and functionally to the individual processes involved to determine their consequences. - Determine mechanisms of human primary immunodeficiencies to mycobacterial infections using the zebrafish. We will model in the zebrafish known human genetic mutations that increase human susceptibility to mycobacterioses to determine their susceptibility mechanisms, particularly in early infection.

Lay Abstract: Tuberculosis remains a major problem in much of the world, sickening ~ 10 million people and killing ~1.4 million per year. This is because the only vaccine is not that effective and six months of multidrug treatment are required for cure, making treatment adherence difficult, especially in poor parts of the world which suffer the most from TB. We think that improved therapies and effective preventions require better understanding of how the TB bacteria cause disease and which host responses to infection are beneficial versus harmful. We have developed the zebrafish as a model for TB, exploiting its optical transparency that allows us to visualize how TB bacteria and host cells interact at each step to cause disease. The zebrafish is amenable to genetic mutation, so we can observe the impact of mutations and determine how they alter infection outcome. Our work is leading to completely new TB treatments.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: Integration of context and task rules by the nucleus reuniens.
Funder: Wellcome Trust

Abstract: Deciding the best way to behave is often dependent on where you are. For example, cheering loudly when someone scores a goal is a good way to behave if you are watching a football match in the pub, but not if you are watching it on your phone in the library.The ability to tell where you are is governed by a part of the brain called the hippocampus, while deciding the most appropriate behaviour is governed by the prefrontal cortex. By communicating intricately with each other, it is proposed that these regions allow you to modify behaviour based on your location. However, the hippocampus and prefrontal cortex are not connected to each other, and therefore we do not understand how they communicate so effectively.In this proposal we will investigate that idea that this communication occurs through a region called the nucleus reuniens. We will investigate how this region connects with both prefrontal cortex and hippocampus; we will carry out computational modelling to investigate how this communication might occur; and then carry out behavioural experiments that will allow us to directly test how neurons in the nucleus reuniens allow the modification of behaviour based on where we are.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: NEUROLOGICAL;MENTAL HEALTH
Award Title: Integrative computational and systems biology approaches for deciphering cellular regulomes that promote carcinogenesis
Funder: Medical Research Council

Abstract: Numerous genetic aberrations affecting a large number of gene products contribute to tumour development and the accepted hallmarks of cancer, often making therapies based on single targets ineffective. These aberrations and their consequences are propagated via transcriptional, translational and post-translational networks. The resultant information circuits can extend across cell and tissue types and also modulate the microenvironment. How to integrate and model this percolation of information and properties across different biological scales, in both time and space is accepted as a major challenge to fully understanding the aetiology, progression and dynamics of tumorigenesis. Novel computational methods, tools and resources are essential to address this challenge.  Transcriptomic and copy number assessment studies suggest that specific sets of key pathways that regulate cellular phenotypes are pathologically altered in cancer. However, pathway centric approaches are not completely effective because pathways don’t operate in isolation; instead, multiple interacting pathways form a complex web of networks. Methods to decipher cellular information flows (whether they are signalling, metabolic or regulatory) can shed light on the underlying cellular complexity and identify systems level properties. The objective of this research programme is therefore to develop a network perspective of tumorigenesis using a mixture of both integrative data driven as well as computational modelling approaches. The programme harnesses data science approaches coupled with computational and systems biology methodologies to develop novel methods, tools and resources for systems level biomedical data-integration. It addresses these objectives by 1) modelling multi-scale cellular regulomes involved in tumorigenesis, 2) developing these model into knowledge discovery systems to assist in understanding of cancer datasets, and 3) Using these resources to elucidate phenotypic impact and identify therapeutic intervention points of these regulomes for further experimental evaluation.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Integrative imaging of brain structure and function in populations and individuals
Funder: Wellcome Trust

Abstract: Neuroimaging enables the mapping of many aspects of the brain’s anatomy, connections, and function. New landmark studies including UK Biobank and the Human Connectome Projects are taking neuroimaging to the scale of populations. Such studies deploy multiple imaging modalities with the aim of learning more about the brain, and identifying imaging markers relevant to neurological disease. However, we cannot currently take full advantage of the richness of these new resources, including:  major advances in the quality of data;  complementarity of multi-modal imaging;  large subject numbers;  and linked information about health outcomes, genetics and risk factors.   Our vision is to extend the reach of imaging neuroscience. This requires new research across multiple domains: from integrated cross-modal analysis, to more detailed and biologically-interpretable markers, to machine learning. We aim to enable neuroimaging to achieve its full potential, from the modelling of variation in populations to the characterisation of individual subjects.   We will deliver powerful modelling approaches and research platforms, continuing our long track record of disseminating software for use by basic and clinical neuroscientists. Further, we will leverage our leadership in big data projects to demonstrate how these approaches and computational tools can advance our understanding of the brain and its diseases.

Lay Abstract: Neuroscientists and doctors use neuroimaging to study the brain without cutting into it. We can see different brain tissues, map brain connections, and even watch brain activity in real time.  To discover more about how the brain works, and how diseases occur in the brain, Big Data imaging studies of thousands of volunteers are now underway. However, imaging neuroscientists are not yet able to take full advantage of such huge, high-resolution, and complex datasets - for example to detect disease early enough to treat successfully.  Using new imaging neuroscience and Artificial Intelligence (AI) research, we aim to learn much more about how the brain varies across different people, and changes with disease. We aim to bring our research together with the new big datasets so that we can even learn how to predict disease in new patients in the future.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: MENTAL HEALTH;GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Award Title: Intercellular transfer of therapeutic DNA for gene and cancer therapies
Funder: Innovate UK

Abstract: Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.


Research Activity Codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health Categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Award Title: Interim grant funding agreement - Accelerating detection of disease (ADD) Challenge
Funder: Medical Research Council

Abstract: https://ourfuturehealth.org.uk/ Our Future Health will be the UK’s largest ever health research programme, bringing people together to develop new ways to prevent, detect and treat diseases. To deliver the outcomes and benefits of the ADD Challenge, the Challenge will build a cohort of 5 million individuals donating biological and digital data to support research on early detection and improved risk stratification of diseases and create a testbed for healthcare innovation.  Early identification of disease will enable earlier intervention and thus more treatment options including the implementation of the prevention measures to improve outcomes and public health.  The Challenge will position the UK as a world leader for early detection and prevention research and provide an urgently needed platform for the development and validation of new diagnostic tests and technologies. An additional phase of the project increased the level of support to develop the OFH Database.


Research Activity Codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Interleukin-1β Protects Against Multi-Organ Endothelial Injury.
Funder: Chief Scientist Office, Scotland

Abstract: Multi-organ endothelial dysfunction, often presenting as thrombotic microangiopathy, is typical of numerous potentially fatal conditions including accelerated hypertension, pre-eclampsia, vasculitis and antibody-mediated transplant rejection, as well as being a complication of treatment with vascular-endothelial growth factor (VEGF) inhibitors. Severe injury may occur in the brain, eye, heart and kidney through shared mechanisms that remain poorly defined. The inflammasome is a component of the innate immune system present in myeloid cells, and its activation results in the production of the pro-inflammatory cytokine interleukin-1β (IL-1β). IL-1β antagonism is used to treat a range of auto-inflammatory diseases and has recently been suggested as a therapeutic strategy in atherosclerosis. My preliminary data suggest a novel protective role for IL-1β from multi_x0002_organ endothelial dysfunction. These effects appear to be mediated through the VEGF system. This fellowship will explore these findings more deeply and help to gain better mechanistic insights into the results of previous clinical trials. It will also start to define the potential for IL-1β to act as a clinical disease biomarker and for the pathways involved in its generation as targets for novel therapeutic interventions.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: CARDIOVASCULAR
Award Title: Internet-delivered Cognitive Therapy (iCT) for young people with Post Traumatic Stress Disorder (PTSD)
Funder: Medical Research Council

Abstract: Need. Post-Traumatic Stress Disorder (PTSD) in youth is a common problem in the UK and globally. Most young people are exposed to traumatic events before they are 18 years old; about 15% will develop PTSD which may persist for years if untreated. PTSD is associated with impaired social and academic functioning, poor quality of life, increased suicidal behaviour, and significant comorbidity. Highly effective psychological treatments exist but are not commonly available in the NHS. There is an urgent need to disseminate these effective treatments for PTSD in youth. Solution. We will build software for an Internet-delivered version of our effective face-to-face Cognitive Therapy for PTSD, which will be accessible online via computers, tablets, and smart-phones. Internet delivered Cognitive Therapy (iCT) for PTSD offers huge potential for very wide, cost-effective dissemination of a highly effective treatment. Rationale. We have developed a specialist treatment, Cognitive Therapy for PTSD, and shown in 2 RCTs that it is highly effective in treating PTSD when delivered face-to-face to adolescents. We have also developed Computerised CBT (C-CBT) for depression, and shown that it is enthusiastically embraced by adolescents, and clinically effective. Work with adults shows that PTSD is a condition which can be successfully treated with internet-delivered CT. The gap in provision is for internet-delivered CT for PTSD in youth. Plan. The project has 2 phases. In the first phase, we will build software for internet-delivered Cognitive Therapy (iCT) for PTSD. In the second phase, we will evaluate iCT in an RCT (vs Face-to-Face Cognitive Therapy and a Wait List (delayed treatment) condition) to provide feasibility data on acceptability, compliance, retention, and delivery of the intervention, and to provide point estimates of the effect sizes (and confidence intervals) of iCT on PTSD and co-morbid problems.


Research Activity Codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health Categories: MENTAL HEALTH
Award Title: Investigating Biomarkers for the Early Detection of Pancreatic Cancer in Genetically Engineered Mouse Models of New Onset Diabetes-Associated Ductal Adenocarcinoma
Funder: Cancer Research UK

Abstract: Background:
Pancreatic cancer is the most deadly of cancers, and urgent improvements are needed in the management of this disease. There are two reasons for these appalling statistics – a lack of effective treatments, and also a lack of symptoms or markers associated with early disease. Because of the low incidence of pancreatic cancer, screening in the general population is problematic, however, screening in high risk populations is feasible. Patients who present with adult new onset diabetes over the age of 50 have ~1% chance of being diagnosed with pancreatic cancer in the following 3 years, making these patients an attractive population for screening. We hypothesise that there are proteins present in the blood of these patients that could be used for early detection. We have developed a mouse model that phenocopies this phenomenon and thus presents a significant opportunity to discover biomarkers for early detection of pancreatic cancer.

Aims:
•	To discover early markers of pancreatic cancer in a mouse model of pre-neoplastic lesion-associated diabetes.
•	To investigate putative biomarkers of early disease across GEMMs models of pancreatic cancer of different genetic backgrounds.
•	To validate pancreatic cancer biomarkers in human pancreatic cancer patient samples.

Methods:
We will use plasma proteomics to investigate biomarkers in the blood of our mouse model of new onset diabetes associated with PDAC, at different stages throughout disease progression. We will also investigate biomarkers in other autochthonous mouse models of pancreatic cancer of different genetic backgrounds, focussing on the small subset of those that present with diabetes. We will interrogate biomarker candidates ex vivo, to determine their source and also if they play any role in pancreatic cancer. Finally, we will validate the most promising biomarkers in human pancreatic cancer patient samples.

How the results of this research will be used:
In pancreatic cancer early detection could have massive impact. If detected at an early stage, when surgical resection of the tumour is possible, the 5-year survival rate is 39%, compared to only 3% in patients with metastasis at diagnosis. Ultimately we propose that a test for the most specific and sensitive biomarker identified by our research could be made available for screening in high risk individuals, particularly cases of new onset diabetes.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS
Award Title: Investigating SARS-CoV-2 Transmission in UK Jewish Communities
Funder: Medical Research Council

Abstract: This study, in a UK Jewish community, will investigate the role of children, cross-protection from non-SARS-CoV2 coronaviruses, asymptomatic transmission, household structure, and pre-existing conditions on transmission and burden of disease. This will generate strong evidence for major unknowns in infection natural history, and by using transmission models we can translate findings to improve UK projections of subsequent waves. Uniquely this community has maintained community level records on treatment both within and outside the home for all members providing an unparalleled record of the impact of COVID-19 and combined with their highly-connected population structures and large inter-generational household structures make them an ideal case-study in understanding drivers of transmission in high-risk communities and in particular the role and/or risks associated with children. We will undertake a cross-sectional survey enrolling 500 households. We will collect information on household structure, social mixing, evidence of COVID-19 and collect samples for serological testing for SARS-CoV-2 and HCOV infection. We will collect detailed data on community understanding and perceptions of risk and acceptability and feasibility of future control strategies such as vaccination. We will use these data to fit a mathematical transmission model of SARS-CoV-2 and  estimate risk of each transmission in different settings, such as households, schools, synagogues and yeshiva, which is critical as the community (and the country) exit lockdown. By analysing households, we will quantify transmission from children, by comparing the force of infection by household size and composition. This information is critical for re-opening of schools in the Autumn.


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health Categories: INFECTION