NIHRDataInsights/HRCSData huggingface dataset:
Award Title: The role of GABAergic inhibition in the function and dysfunction of the human binocular visual system
Funder: Medical Research Council

Abstract: The ability to see in-depth using two eyes is acquired early in development, and critically requires normal binocular visual experience. Abnormal binocular experience, through a squint or unequal refraction, causes long-lasting and severe deficits in visual perception. This condition called Amblyopia,  affects around 3% of the population. As binocular vision is achieved by the brain, amblyopia is a disorder not of the eyes but of the brain. One of the key elements in determining experience-dependent plasticity in the binocular visual system is the inhibitory neurotransmitter GABA. This programme of research is designed to determine the role of GABA in binocular function and dysfunction in the human visual cortex.   The proposed research aims to use multi-modal magnetic resonance imaging (MRI) to determine (i) whether pharmacologically modulating GABA levels in the brain interferes with binocular functions; (ii) whether a binocular visual training  leads to a reduction in GABA in amblyopes that is correlated with improvement in binocular vision and; (iii) how the visual system of children at risk of amblyopia differs from those without binocular deficits and how patching therapy changes cortical structure and function underlying binocular vision.      In combination, we will non-invasively quantify the concentration of GABA in the visual cortex, obtain population receptive field measures of depth and assess binocular vision acuity to determine the relationship between neurochemistry, neural organisation and perception. By performing experiments in healthy adults, adults with amblyopia and children at risk of amblyopia, we aim to build a unifying framework that can account for changes during early development and in adulthood. Not only will these studies provide important data for improving therapy for amblyopia, but the binocular vision system can act as a model for neurodevelopmental disorders of higher cognitive function, such as autism or schizophrenia.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: EYE;NEUROLOGICAL
Award Title: The role of axonal mRNA translation in Amyotrophic Lateral Sclerosis (resubmission)
Funder: Medical Research Council

Abstract: Dysregulated RNA biology has emerged as a major driving force in the pathogenesis of Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. While it is still unclear why motor nerves are particularly vulnerable in ALS, their extreme length further implicates axonal trafficking processes to be involved. The observed 'dying-back' pathology also supports that cellular disruption begins at the distal nerve terminus. Thus, we hypothesise that defects in processes such as transport and translation of certain mRNAs in motor neurons is an important contributor to neurodegeneration in ALS. In this proposal we aim to identify mRNA populations actively undergoing translation (translatome) specifically in the axons and synapses of motor nerves in vivo. We will use the model organism Drosophila to study the disease-relevant neuron type in situ, and to exploit its unparalleled genetic tractability. We have established a novel method to extract tagged ribosomes specifically from motor nerve axons. In this study, we will 1) determine the MN axonal translatome under normal conditions over the fly life-course, 2) investigate how axonal and somal translation is affected by TDP-43 mutations and C9orf72-related repeats during disease progression and 3) determine the relative contribution of different dysregulated axonal mRNAs to pathogenicity by assessing their functional impact on the disease-relevant circuits at an organismal level. The results of this project will provide new insights into how dysregulated RNA biology specifically impacts on motor neuron survival.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health Categories: CONGENITAL DISORDERS;NEUROLOGICAL
Award Title: The role of family background for individuals’ material and psychological wellbeing
Funder: The British Academy

Abstract: The extent to which individuals’ life chances depend on family circumstances is a fundamental question of social science. Circumstances of families and their adult children are typically defined in terms of income, social class, or education. Such broad categories, however, might not fully capture how family circumstances define individuals’ life chances. In this project I will extend knowledge on both the types of advantages and disadvantages that are intergenerationally reproduced and through which channels this occurs. First, this study will examine the implications of family background on various dimensions of material and psychosocial wellbeing. Material wellbeing is defined in terms of wealth, financial burdens and financial stress while psychological wellbeing is defined in terms of mental health and life satisfaction. Second, I will take a multidimensional approach to social origin and study what particular dimensions of family context are important for adult wellbeing. The project will focus on the UK in an international comparative perspective.


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health Categories: MENTAL HEALTH
Award Title: The role of impaired glucagon secretion in life-threatening hypoglycaemia of type 1 diabetes: mechanism and therapeutic potential
Funder: Medical Research Council

Abstract: Glucagon is the body's principal hyperglycaemic hormone and acts by stimulating hepatic glucose production. It is released from the alpha-cells of the pancreatic islets in response to neurotransmitters (like adrenaline) and a fall in plasma glucose below the normal 5mM but inhibited by somatostatin (released from neighbouring delta-cells).  Type-1 diabetes (T1D) is a bihormonal disorder involving (nearly) complete loss of insulin secretion. Crucially, in T1D glucagon secretion in response to hypoglycemia also becomes defective. This increases the risk of severe hypoglycaemia, a potentially fatal complication of insulin therapy. Hypoglycaemia accounts for 10% of the mortality in patients with T1D. The only effective treatment (apart from reducing insulin) is islet or pancreas transplantation but the requirement for immunosuppression makes this a last resort.  We will explore the mechanisms underlying the defective glucagon secretion in T1D using in vivo (insulin tolerance tests) and ex vio techniques (hormone secretion, electrophysiology, imaging, gene expression analysis). For our experiment we will use the NOD mouse model, which previously has been widely used for studies of autoimmune destruction of the beta-cells but with little attention being paid to the alpha- and delta-cells that survive the autoimmune attack.  Preliminary data indicate that NOD mice recapitulate the loss of hypoglycaemia-induced glucagon secretion seen in patients wit. We will explore how the autoimmune attack, and/or the subsequent reorganisation of the islet and resultant hyperglycaemia results in dysregulated glucagon secretion.  The proposed studies will result in  new therapeutic paradigms that reduce the risk of hypoglycaemia, thereby enabling more aggressive insulin therapy that reduce the risk of secondary microvascular complications (including heart/renal failure).


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: METABOLIC AND ENDOCRINE
Award Title: The role of serum derived-extracellular vesicles in development and treatment of stroke and cognitive impairment
Funder: Chief Scientist Office, Scotland

Abstract: Stroke is the 3rd leading cause of death and The leading cause of disability in the UK. Stroke risk increases with age and as we are living longer the number of people living with the consequences of stroke increases. One of the most feared consequences of stroke is memory problems. Our research group looks for new stroke treatments. Extracellular vesicles (EVs) are tiny particles that transport messages around the body. EVs have roles in both health and disease. We have found that EVs in blood from people with stroke differ from those in people without stroke. The main difference is in the types of microRNA (miRNA) they carry. MiRNAs are small pieces of a person's genetic make-up which control the expression of other substances. In this study we will explore how these miRNAs differ in people with stroke. We will particularly focus on those with stroke related memory problems. We will then test whether adding 'healthy' miRNA to EVs can aid recovery in experimental stroke models. If we show that miRNA can lessen the damage from stroke, both physical function but also memory and thinking, there may be scope to develop new treatments.


Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: STROKE
Award Title: The systems biology of oncogenic PI3Kα-driven stemness regulation
Funder: Wellcome Trust

Abstract: Cancer stemness is linked to therapy resistance and metastasis. Emerging evidence suggests that PIK3CA-H1047R, a hotspot mutation in breast cancer and the PIK3CA-related overgrowth spectrum (PROS), elicits a stemness phenotype characterised by dedifferentiation and cell plasticity. Nevertheless, PIK3CA-H1047R does not cause malignancy in PROS, perhaps reflecting molecular differences between mammary (cancer) and endothelial (PROS) cell lineages. 

By learning and applying novel systems biology tools, I aim to address the mechanism(s) behind PIK3CA-H1047R-driven stemness in a quantitative manner, taking into account cell type, genetic mosaicism and the strength of genetic PI3K pathway activation. I will generate mosaic cell models with doxycycline-inducible PIK3CA-H1047R expression, focussing on human breast epithelial cells and human endothelial cells due to their relevance for breast cancer and PROS, respectively. The cells will be exposed to short- and long-term PIK3CA-H1047R expression, followed by temporal assessment of: 1.Cell-state-transitions by single-cell RNA sequencing; 2.PI3K signalling dynamics by candidate-based quantitative single-cell imaging. Next, I will use data integration and mathematical modelling to infer the underlying regulatory principles. My ultimate goal is the identification of PIK3CA-mutant- and cell type-specific pharmacological therapies for reversal of aberrant stemness regulation, followed by validation in physiologically-relevant 3D models based on the established mosaic cell systems.

Lay Abstract: Defects in a gene known as PIK3CA are common in breast cancer and in developmental disorders featuring vascular malformations. In these conditions, cells with a PIK3CA mutation are out of tune with their environment and misinterpret the signals they receive. Research suggests that this misinterpretation may result in a loss of cell identity, whereby a cell becomes more 'plastic' and harder to eradicate with conventional therapies. Taking an engineering view, I propose to study the cell as a 'computational system' in order to understand how PIK3CA is wired to regulate cell plasticity, and how this changes according to different conditions - specifically focussing on models of the breast and the vasculature. To succeed, I will collaborate with drug development experts and computer scientists who will teach me how to analyse new types of experimental data that can be used to predict optimal therapeutic strategies for cells with genetic PIK3CA defects.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: The use of Advanced MRI techniques to evaluate antenatal lung development.
Funder: Medical Research Council

Abstract: Pulmonary hypoplasia is a congenital condition in which development of the lungs is incomplete. This results in lungs that are too small for efficient gas exchange in postnatal life. It affects 1:1000 pregnancies and is lethal in over 50% of cases. It is associated with conditions such as second trimester premature rupture of membranes, congenital diaphragmatic hernia or certain congenital heart diseases. At present ultrasound and conventional MRI scans provide the mainstay of antenatal lung assessment and are used to prognosticate whether the child is likely to survive.  However these scans only evaluate overall lung size and do not provide insight into tissue microstructure or function. Advanced MRI techniques (deformable slice to volume reconstruction, motion corrected diffusion and T2* imaging) facilitate more accurate assessment of lung size and vasculature, and can assess tissue microstructure and oxygenation potentially reflecting alveolar structure and tissue perfusion. This project aims to evaluate lung development with advanced MRI techniques in uncomplicated pregnancies and those at high risk of pulmonary hypoplasia. Methods 100 women with uncomplicated pregnancies and 70 with conditions at high risk of pulmonary hypoplasia will be recruited from four tertiary referral units. MRI imaging will be undertaken including T2, T2* and diffusion sequences. Outcome data including survival, surgical interventions, surfactant or supplemental oxygen therapy will be recorded. Pulmonary function tests will be performed at term equivalent age from three units. Data will be postprocessed to generate lung volumes, mean T2*, fractional anisotropy and apparent diffusion co-efficients. Normal ranges during gestation for each parameter will be generated and conditions at high risk of pulmonary hypoplasia will then be compared. In the future we hope this knowledge may help improve and individualize counselling, and evaluate surgical and medical interventions.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: CARDIOVASCULAR;REPRODUCTIVE HEALTH AND CHILDBIRTH
Award Title: The use of global connectivity estimates in real-time models of international infectious disease spread
Funder: Wellcome Trust

Abstract: Human mobility plays an important part in the spread of infectious diseases. Mathematical models can assess the risk that an emerging outbreak will spread internationally, providing decision-makers with information to support early surveillance and control measures. In this project I will aim to improve how well these models capture international mobility patterns by exploring the suitability of different measures of connectivity. I will compare flight passenger data (which is commonly used in international infectious disease spread models) with alternative transport passenger statistics and novel data, such as location data from mobile phones. I will use these data sources (both individually and in combination) in models to make predictions of the risks of imported and exported disease cases, and assess how well these different models can retrospectively predict the global spread of COVID-19. I will use these findings to develop a statistical model and tools that are ready in advance of future outbreaks to make rapid assessments of the risks that they will spread geographically. The project will lead to more realistic models of international infectious disease spread and thus improve the information that is available to support decision-makers in controlling future outbreaks before they become widespread.


Research Activity Codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION
Award Title: Time critical precision medicine for acute critical illness using treatable trait principles: Data enabled adaptive platform trial with embedded biological characterisation [TRAITS Program]
Funder: Chief Scientist Office, Scotland

Abstract: Our project aims to enable time-critical precision medicine (TCPM) to be used in critically ill patients presenting to emergency departments and Intensive Care Units (ICUs) throughout Scotland. We will develop a collaborative hub based at The University of Edinburgh, to carry out PM Randomised Clinical Trials (RCTs)  (supported by data from the NHS). This will mean TCPM can be potentially used at the bedside within 5 years from start of this project. 

Precision Medicine (PM) refers to treatments that take individual variability into account. PM is growing in use in cancer care, providing precise treatments for patients based on their genetics or proteins. Currently, it isn’t used in ICU because patients admitted to ICU have life threatening illnesses that need treatment immediately and despite current treatment approaches 40% die within 60-days of admission to ICU.

In this project, to enable TCPM in ICU, we have designed a novel clinical trial that will use  routinely collected data and test multiple treatments simultaneously.  To select patients for this TCPM trial, we will use the results of a blood test done routinely in all patients admitted to ICU needing breathing support, namely low lymphocyte counts.  

We plan to assess whether the two lead treatments (recombinant IL-7 and trimodulin) improve survival when administered with usual care. There is preliminary evidence that reversing the effects low lymphocyte count with these two treatments may improve survival in ICU patients.

Consent to participate will be from patients, or their Legal Representative where patients lack capacity. Knowing what happens to participants after they have been recruited is important. Our patient assessments will include short-term outcomes (such as mortality, health related quality of life) and longer-term outcomes such as rehospitalisation. By using routinely collected NHS data to help us understand what happens to patients after they have been discharged from ICU, we will be reducing the burden of trial follow-up for patients.


Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: RESPIRATORY
Award Title: Towards an in vivo functional dissection of the role of microglia and macrophages in Alzheimer’s disease aetiology
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK.  Funding details for UK DRI programmes will be added in 2019. In vivo study of microglia/MØ function is essential to understand how alterations in basic physiological processes, mostly implicated by the genetics of disease (from cell signalling, endocytosis and phagocytosis, lysosomal functions, adhesion and migration, proliferation and renewal), contribute to dysfunctions that may predispose to disease. The in vivo context is essential for the study of MØ phenotype (discussed below), provides a bridge between cell culture and 3d models and human disease, and importantly is amenable to study of disease alterations and testing of potential therapeutic interventions. A collaboration has been established with Gareth Howell (GH) at the Jackson Laboratories (Honorary Cardiff Senior Research Fellow), who has a large US National Institute of Ageing-funded AD model generation programme. Based on Prof. Williams’ observations, GH introduced the protective SNP from PLCG2 into the corresponding highly conserved sequenced in mouse Plcg2 using CRISPR technologies in C57BL/6 mice. The fertility of these mice has been confirmed and they should be shipped to Cardiff in Q2 of 2017. Our collaboration places us in a strong position to rapidly move from identification of novel disease associated variants (Prof. Williams’ ongoing independent genetic discovery programme) to generation of novel mouse models for in vivo dissection of their mechanistic role in diseases susceptibility or protection.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Tracking Cancer Evolution through Therapy (Tracer X)
Funder: Cancer Research UK

Abstract: TRACERx is an international prospective observational clinical trial with 6 confirmed participating Experimental Medicine Cancer Centres (ECMCs).

TRACERx will study the
non-small cell lung cancer (NSCLC) evolutionary mutational landscape and the dynamics of intratumour heterogeneity (ITH) over time combined with detailed clinical and histopathological annotation for each patient. TRACERx will acquire tissue following informed consent from sites of metastatic disease, as part of routine clinical practice, during the disease course for genetic analysis to track the tumour evolutionary dynamics.

 We anticipate that serial exome re-sequencing technologies together with low coverage whole genome ‘skim’ sequencing, to decipher structural rearrangements such as the EML4-ALK and ROS1 fusion genes, will help decipher the frequency of branched evolutionary growth in NSCLCs, and when in the metastatic process distinct somatic events and the initiation of genomic instability are acquired.

 Our goal is to identify the impact of ITH upon clinical outcome, trace the dynamics of tumour evolution over time through non-invasive approaches and ultimately through deciphering tumour evolution on a patient-by-patient basis develop a better understanding of the genetic events that contribute to drug resistance, metastases and tumour adaptation. The relationships between heterogeneous tumour neo-antigen expression and immune effector cell tumour infiltration will also be established. Characterising ITH with sequential tumour biopsies and blood-based analyses of tumour DNA over time will enable us to study the capacity of adjuvant therapies to exacerbate genomic instability and to identify novel factors implicated in drug resistance, tumour metastasis and immune cell effector function driven by tumour neo-antigen exposure. Finally, by mapping tumour growth in greater detail and reconstructing evolutionary histories of individual tumours, we hope to identify mechanisms contributing to ITH in NSCLC. Anonymised but clinically annotated data from these analyses will be made publicly available to enable dissemination to the wider scientific community.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: Tracking and evaluating outcomes from Ambitious about Autism's Education to Employment initiative (Bath)
Funder: Autistica

Abstract: Evaluating AaA's programme which aims to support autistic people in higher education into employment.

Lay Abstract: Evaluating AaA's programme which aims to support autistic people in higher education into employment.

Research Activity Codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE;7.1 INDIVIDUAL CARE NEEDS
Health Categories: MENTAL HEALTH