NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Imaging and activation of glymphatic clearance: a novel strategy for Alzheimer’s Disease
Funder: Wellcome Trust

Abstract: There is a critical need for early and accurate biomarkers of the pre-symptomatic phase of Alzheimer's disease (AD), to maximise the efficacy of emerging therapies. Recent evidence implicates cerebral glymphatic exchange as a key mechanism in early AD pathogenesis [Figure 1] [1-4]. I will develop the first non-invasive method for the quantitative assessment of glymphatic clearance, using MRI. These novel methods will be carefully validated by comparison with the invasive measures [5], that I have previously established, in normal, aged and AQP4 null mice. I will apply these novel techniques longitudinally to mouse models of ageing and AD (amyloid and tau) to investigate impairment of glymphatic clearance relative to more established markers of AD pathogenesis such as structural imaging, perfusion and histological assessment of plaque/tangle burden. As such, these data will be the first to elucidate the chronology of abnormal glymphatic clearance in AD pathogenesis. Finally, I will combine these methods with targeted optogenetics to assess the interaction of vessel tone and vasomotion to rates of glymphatic clearance in order to characterise the underlying mechanisms that drive CSF-ISF exchange.

Lay Abstract: Alzheimer’s disease is a devastating illness that causes severe memory loss. Despite the huge social, economic and emotional burden of the condition, there is currently no cure. The development of effective treatments is hindered by the difficulty of accurately identifying the early phase of the disease, years before symptoms become apparent.
 
Recent evidence has come to light, from experiments performed in the rodent brain, of a previously unrecognised “waste removal” system that clears excess fluid and toxins from the brain. It is thought that impairment of this pathway, known as the “glymphatic” system, may be a critical causal factor in the development of Alzheimer’s disease. However, currently this pathway cannot be measured in humans.
 
I will develop the first non-invasive method to image the glymphatic system using MRI, enabling assessment in the human brain for the first time. This method will be used to better understand how impairment of the glymphatic system contributes to Alzheimer’s disease and how this may be affected by the changes in properties of the brain blood vessels. Taken together, this proposal may lead to a new method for early detection of Alzheimer’s disease and identify a new target for effective drug treatment .

Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: NEUROLOGICAL
Award Title: Immune Sexual Dimorphism in HIV-1 Infection
Funder: Wellcome Trust

Abstract: A HIV positive mother is almost two-fold more likely to transmit her infection to a female foetus than a male in-utero. Females have two X-chromosomes which encode several immunological factors. Usually the second is silenced but some genes escape this and are more highly expressed in females. One example is TLR7, a sensor for interferon (IFN), our strongest innate antiviral response. Preliminary data supports the hypothesis that the female immune system, through greater IFN production, selects for IFN-resistant HIV viruses that replicate with lower capacity than IFN-sensitive viruses, which we propose are transmitted to males. Placental macrophages, Hofbauer cells (HC) express all required receptors for HIV infection and sit at the interface of maternal and foetal blood. We propose they are involved in in-utero HIV transmission and differ between female and male foetuses to explain sex discordance in in-utero HIV susceptibility. 
 
We plan to investigate IFN-resistance and viral replicative capacity of HIV transmitted heterosexually between adults, then ascertain whether HC’s differ in HIV-susceptibility between female and male placentae.
 
By attributing IFN and/or HC a role in the reduced male in-utero HIV susceptibility relative to females, we will explain how HIV crosses the placenta and can start working to prevent it.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH
Award Title: Immunometabolic cross-talk in the inflamed diabetic heart
Funder: Wellcome Trust

Abstract: Diabetic cardiomyopathy (dbCM) is a complication of type II diabetes (T2D), characterised by systemic inflammation, impaired cardiac function and disrupted metabolism. However, the impact of systemic inflammation on the development of the myocardial inflammation and cardiac metabolic derangement that lead to dbCM remain unknown. This study will address how chronic adaptive inflammation driven by systemic metabolic stress in T2D causes cardiac dysfunction. Specifically, I hypothesise that it is caused by inflammation due to T-cell infiltration and not by direct metabolic perturbations that can lead to impaired energetics (reduced PCr/ATP ratio). Specifically, the aim is to use integrated experimental approach combining metabolic analysis with T-cell phenotypic profiling in murine and human T2D to address three research challenges:
 
A. Does infiltration of cardiotropic T-cells impair cardiac substrate plasticity and energetics in dbCM?
 
B. Do myocardial succinate efflux and signalling via SUCNR1 promote cardiac Teff and/or Treg activation by modifying T-cell metabolism and do they enhance pro-inflammatory T-cell differentiation?
 
C. Does stimulation of GCK-mediated glycolysis increase regulatory T-cell migration to the heart causing a switch in the nature of immune response from pro-inflammatory to immunosuppressive? Does the resultant reduction in myocardial exposure to pro-inflammatory cytokines improve cardiac function and mitochondrial performance?

Lay Abstract: While the exact causes of diabetes are still not fully understood, the link between obesity and type-2-diabetes (T2D) is firmly established.Progression of T2D disrupts the supply of energy to the heart causing it to fail. Obesity triggers changes to the body’s metabolism including fat tissue releasing fat molecules into the blood and activating type of immune cells called T-cells.T-cells migrate causing inflammation in many parts of the body.Within heart cells, the energy from food is released by cell components called mitochondria.Problems with mitochondria contribute to  T2D but what initiates them is unknown.I will examine whether T cells cause heart inflammation in T2D and whether this leads to faulty mitochondria and shortage of energy supply.Currently, there is no treatment to improve heart energy supply in T2D.I propose to develop a new metabolic therapy to prevent destruction of energy supply to the heart by reducing the recruitment of  inflammation-causing T-cells in T2D.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM;METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Award Title: Immunotherapy and clear cell ovarian cancer
Funder: Medical Research Council

Abstract: Clear cell ovarian cancer (CCOC) displays a chemo-resistant phenotype and patients with advanced disease have a poor overall survival.  Four of five patients with advanced, heavily pre-treated CCOC had a complete or partial response following treatment with drugs inhibiting the PD-1 checkpoint however the mechanism behind the anti-tumour response is unknown. In several other cancer types the frequency and location of immune cells in the tumour microenvironment, as well as the levels of overexpression of PD-1/PD-L1 either on the cancer cell or tumour, influence response to checkpoint blockade.  Immune related gene expression signatures (irGES) can also predict response to treatment in certain tumour types.  This proposal has three aims.  First we will undertake a comprehensive analysis of the immune landscape of advanced CCOC biopsies using immunohistochemistry with Definiens digital analysis as well as mass cytometry to profile the quantity of the major populations of immune cells alongside their spatial arrangement.  We will also detail their irGES at baseline via nanoString.  Second, we will use this information to validate the immune landscape of a mouse model of CCOC using the same techniques above and performing a cross species analysis of the results.  Third, we will assess how anti-PD1 therapy changes the immune ecosystem using the techniques described above in samples taken from the mouse model following treatment with anti-PD-1 therapy and in samples from a clinical trial that will provide baseline and on-treat biopsies from patients. These aims will enable us to achieve our overall objective of understanding the mechanism behind response and resistance to anti-PD1 in CCOC in order to devise treatment plans that will improve response rates and duration of response in patients.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Impact of a pea-rich diet on the human gut microbiome, metabolomic profile and gut barrier function
Funder: Wellcome Trust

Abstract: The gut microbiota has a profound impact on host physiology affecting overall health through the fermentation of carbohydrates such as plant polysaccharides (Thursby and Juge, 2017 474:1823). However, little is known about the impact of pulses on the gut microbial metabolism. Previous work at JIC showed that pea mutations in the gene encoding for galactinol—sucrose galactosyltransferase resulted in changes in myoinositol, galactinol and raffinose metabolites in the seeds. This may influence gut microbiota structure and function, where major gut symbionts such as Ruminococcus gnavus can metabolize raffinose family oligosaccharides (RFO) as shown at QIB (Cervera-Tison et al, 2012 78:7720, Lafond et al. 2020 11:579521).Nonetheless, RFO have been associated with discomfort when intestinal fermentation occurs. We want to understand whether the changes  in RFO content in the seeds of pea mutants beneficially affect human gut barrier function and immunity. For this, pea mutants will be characterised and metabolic effects of these mutants will be determined on the faecal microbiota. Finally, functional assays using human-based organoids will be used to assess gut barrier function and immune response.The expected impact of this multidisciplinary work is to select a pea candidate mutant line that could be used for future human intervention studies.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: ORAL AND GASTROINTESTINAL
Award Title: Impact of chemotherapy on anti-cancer immunity in molecularly-stratified subgroups of colorectal cancer- Supported by the Bobby Moore Fund
Funder: Cancer Research UK

Abstract: Background
Adjuvant chemotherapy improves overall survival (OS) in only 3-4% of stage II and 15-20% of stage III colorectal cancer (CRC). Thus, biomarkers are urgently needed to select patients who should be given adjuvant chemotherapy; this has become even more relevant given our recent data which suggest that a subgroup of stage II/III patients defined by microsatellite instability (MSI) status and high expression of the immune checkpoint regulator PD-L1 derive no benefit and may even be harmed by 5FU-based chemotherapy. The median OS for advanced disease (stage IV) patients is currently less than 30 months, and 5-year OS rates are 6%. The recent success of cancer immunotherapy in a number of cancer has demonstrated the clinical effectiveness of reactivating anti-tumour immune responses, but so far, immunotherapies have only demonstrated activity in the small subset (~4%) of stage IV CRC patients with MSI disease.

Aims and Methods
Combining chemotherapy with immunomodulatory drugs is widely recognised as having great therapeutic potential in a range of cancers, and many clinical trials are underway. The challenge of realising the potential of such approaches in CRC is to understand the immunomodulatory effects of chemotherapy in specific molecular subgroups so that rational combinations with immune-oncology (IO) agents can be implemented in selected patient populations. In this programme, we will use clinically relevant disease models and integrative multi-omics analyses of colorectal tumours to explore the following main aims:

1. Validate that the PD-L1(high) subgroup of early stage CRC represents a distinct clinical subgroup that fails to benefit from 5FU-based chemotherapy that may instead benefit from anti-PD-L1 immunotherapy.
2. Investigate the impact of 5FU-based chemotherapy on tumour-intrinsic immunomodulatory signalling in specific molecular and genetic subgroups of CRC.
3. Assess the impact of epigenetic modifying agents (EMAs) such as HDAC inhibitors on tumour cell death and anti-tumour immunity when used alone and in combination with chemotherapy in molecularly-defined CRC.
4. Determine the efficacy of using IO agents such as PD-L1 in a targeted manner to exploit the immunomodulatory effects induced by chemotherapy and EMAs in molecularly-defined subsets of CRC.

How the results of this research will be used
The overall goals of this programme are to identify immunomodulatory signals/biomarkers in CRC that are constitutively expressed and/or induced in clinically important genetic contexts by chemotherapeutic agents and explore the potential of using epigenetic and immunomodulatory therapies in combination with standard chemotherapy in these specific molecular subgroups.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: Impact of socioeconomic circumstances on risks and life-course consequences of preterm birth: studies into differential exposure and susceptibility
Funder: Medical Research Council

Abstract: Aims To identify the causal pathways from maternal socioeconomic status to preterm birth. To explain and quantify the interaction between preterm birth and socioeconomic conditions on later life health and educational inequalities. To evaluate the potential effectiveness of policy or intervention on reducing inequalities in preterm birth prevalence and health and educational outcomes in later life. Three research questions have been identified: 1- How do key exposures, such as maternal health and behaviours, mediate the pathway from maternal socioeconomic status to preterm birth? 2- How does preterm birth influence the relationship between maternal socioeconomic status and adolescent outcomes for health and education? 3- What is the effect of interventions to improve birth outcomes, and outcomes for children born preterm, on later life inequalities associated with socioeconomic circumstances? Methods Secondary analysis of data sources: Millennium Cohort Study (MCS) and the Welsh SAIL databank. The MCS is a birth cohort of almost 19,000 children born in the UK in 2000/01. The SAIL databank is a collection of anonymously linked data across Wales, including birth extracts, health data from primary and secondary care, and educational data. Analysis will be through causal mediation analysis, fourfold decomposition analysis to separate mediated and interactive effects, and simulation of intervention effects. Outcomes will be measured using mortality and morbidity measures (e.g. ICD10 diagnosis), healthcare usage and exam results at Key Stage 3, GCSE and A-Level. Scientific and Medical Opportunities Results will be used to inform policymakers, and Obstetric and Paediatric clinicians of potential intervention points to reduce preterm birth burden, and identify a particularly at risk cohort of children who are currently not supported by policy or intervention in the UK. The results will demonstrate the potential benefits of intervention on later life outcomes.


Research Activity Codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health Categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Award Title: Improved diagnostics in food allergy (ID-in-FA) Study
Funder: Medical Research Council

Abstract: AIM To determine the diagnostic accuracy of two complementary, novel approaches to diagnose food allergy, in a representative clinical cohort. BACKGROUND Food allergy is an increasing public health issue affecting up to 6% of UK children, and can cause life-threatening anaphylaxis. Conventional tests assess the presence of allergen-specific IgE ("sensitisation") rather than true clinical reactivity, and are associated with a false positive rate of over 50%. This results in over-diagnosis, causing unnecessary dietary/social restrictions and anxiety. Improved diagnostics which can be performed in the outpatient setting are thus an important goal. METHODS We will recruit children with indeterminate allergic status despite conventional testing, recruited from our specialist clinic and undergoing open, oral food challenge (FC) to clarify a diagnosis of food allergy to peanut, egg or cow's milk. Skin prick testing, blood tests (incl. components) will be performed immediately prior to oral FC, together with: 1. Intranasal food challenge - a straightforward procedure in which low doses of food protein are administered into the nasal mucosa, causing a mild hay fever-like response in allergic but not non-allergic individuals. 2. Mast cell activation test (MAT) - in which patient sera are incubated with primary human mast cells and subsequently stimulated by allergen in vitro: pilot data indicates this is a robust test, with excellent diagnostic performance. The results of these tests will be compared to conventional tests, using Receiver Operating Characteristic curve analysis (with oral FC as the gold standard). TRANSLATIONAL CAPABILITY Pilot data indicates both techniques confer significant diagnostic accuracy over existing conventional testing. This study will provide the necessary validation to secure follow-on translational funding and commercial investment, to accelerate product development through to regulatory approvals and ultimately clinical use.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Improving Mental Health Literacy Among Young People aged 12-15 years in Indonesia: IMPeTUs
Funder: Medical Research Council

Abstract: Depression is the leading cause of disease burden in low-to-middle income countries. The World Health Organisation has engaged in a programme of scaling-up mental health services, but significant challenges remain. Improving mental health literacy in children and young people, a core part of recent, global health strategies has the potential to address some of these challenges. The aim of this study is to co-develop and feasibility test, a culturally-appropriate toolkit to promote depression-focused mental health literacy and self-management skills in Indonesia, for children aged 12-15 years. This mixed methods study will comprise four phases.  Phase 1 (a systematic review of peer reviewed studies and grey literature) will identify the range of approaches to mental health literacy and depression self-management and critically review current evidence regarding intervention effect.  Phase 2 will comprise semi-structured interviews with key stakeholders including policy makers, clinicians, teachers, adolescent service users, carers and young people aged 12-15 years to explore their views on depression and identify priorities for the intervention. Photo elicitation methods will be incorporated into interviews with children and young people. Phase 3 will comprise iterative workshops with local stakeholders to present our findings and co-produce a testable, culturally appropriate toolkit to promote mental health literacy and depression focused self-management in 12-15 year olds in Java, Indonesia.  In phase 4, we will undertake nine in-depth case studies to compare three different implementation pathways (ie. schools, CAMHS services and primary care centres) in three geographically different areas in terms of levels of culture, urbanisation and health service development (Jakarta, Bogor and Magelang). We will examine the impact, acceptability and feasibility of our prototype intervention and produce evidence-based guidelines for wider implementation.


Research Activity Codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL;6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health Categories: MENTAL HEALTH
Award Title: Improving Teacher Retention
Funder: Wellcome Trust

Abstract: To fund a partnership with EEF to deliver a funding scheme with supporting activities that is intended to support the development and testing of interventions aimed at improving the retention of science teachers in secondary schools. The aims of the Programme are to:
a) build an evidence base on the most effective ways of improving science teacher retention, ensuring any findings are shared across the country, and particularly in areas of disadvantage; and
b) ensure the results of this work are accessible to policymakers and practitioners.


Research Activity Codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health Categories: GENERIC HEALTH RELEVANCE