NIHRDataInsights/HRCSData huggingface dataset:
Award Title: INSULIN SENSING IN THE BRAIN AND THE EFFECTS OF INSULIN RESISTANCE ON METABOLIC BEHAVIOUR
Funder: Medical Research Council

Abstract: The brain Dorsal Vagal Complex (DVC) senses insulin to regulate glucose metabolism and feeding behavior in rodents. Obesity causes insulin resistance and completely disrupts the regulative functions of the CNS. Three days of high-fat diet feeding is sufficient to cause insulin resistance in the DVC by increasing mitochondria fission and ER stress. This leads to rising blood glucose levels and food intake. I aim to understand the molecular events that trigger insulin resistance in the DVC. To achieve this, I will use a combination of molecular and chemical tools coupled with mass spectrometry analyses to identify new target molecules involved in developing brain insulin resistance in animals. I will also use in vivo readouts, including glucose clamp and feeding studies, to understand the effects that insulin resistance has on whole-body glucose metabolism and feeding behavior. The neuronal population(s) involved in these processes are unknown. I will identify the neuronal networks that sense insulin in the DVC and regulate metabolic functions in rats by using a combination of genetic models with immunohistochemistry and electrophysiology techniques.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: MENTAL HEALTH;METABOLIC AND ENDOCRINE;NEUROLOGICAL
Award Title: Iatrogenic cerebral amyloid angiopathy and intracerebral haemorrhage
Funder: Stroke Association

Abstract: Iatrogenic amyloid-beta cerebral amyloid angiopathy (iCAA) is associated with intracerebral haemorrhage in young patients with a history of procedures involving the head and neck in childhood. We hypothesise that these patients acquired amyloid-beta protein during these procedures, as has been demonstrated in animal models. This is a new and emerging disease with significant potential public health implications.

The aim of this programme of research is to further characterise the clinical features and risk factors associated with iCAA, via three feasibility studies:

1.	Clinical surveillance in a population at risk of iCAA:
We will perform detailed clinical and radiological assessments (including blood tests, neuropsychological testing, electroencephalography, MRI, lumbar puncture) of 10 individuals who received cadaveric human growth hormone prepared using the Hartree-modified Wilhelmi procedure, as preparation for a larger surveillance study.

2.	Body fluid biomarkers for iCAA:
We will analyse blood and cerebrospinal fluid from 10 patients with known iCAA in order to identify diagnostic and prognostic biomarkers of interest.

3.	CAA in animal models of amyloid-beta transmission:
We will use inoculation experiments to test our hypothesis that there are different strains of amyloid-beta, and that these strains result in different clinical phenotypes and patterns of disease.

Lay Abstract: Iatrogenic amyloid-beta cerebral amyloid angiopathy (iCAA) is associated with intracerebral haemorrhage in young patients with a history of procedures involving the head and neck in childhood. We hypothesise that these patients acquired amyloid-beta protein during these procedures, as has been demonstrated in animal models. This is a new and emerging disease with significant potential public health implications.

The aim of this programme of research is to further characterise the clinical features and risk factors associated with iCAA, via three feasibility studies:

1.	Clinical surveillance in a population at risk of iCAA:
We will perform detailed clinical and radiological assessments (including blood tests, neuropsychological testing, electroencephalography, MRI, lumbar puncture) of 10 individuals who received cadaveric human growth hormone prepared using the Hartree-modified Wilhelmi procedure, as preparation for a larger surveillance study.

2.	Body fluid biomarkers for iCAA:
We will analyse blood and cerebrospinal fluid from 10 patients with known iCAA in order to identify diagnostic and prognostic biomarkers of interest.

3.	CAA in animal models of amyloid-beta transmission:
We will use inoculation experiments to test our hypothesis that there are different strains of amyloid-beta, and that these strains result in different clinical phenotypes and patterns of disease.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: STROKE
Award Title: Identification and characterisation of host proteins important for human cytomegalovirus
Funder: Wellcome Trust

Abstract: During viral infection, the host cell produces proteins that inhibit viral replication, known as antiviral restriction factors (ARFs). The virus can overcome this inhibition by degrading these proteins. Human cytomegalovirus (HCMV) is a herpesvirus that successfully evades the hosts antiviral response and establishes life-long latent infection. I aim to investigate the interaction between host and viral proteins in order to identify factors important for host defense against HCMV infection. I will use proteomics to map the network of virus-host interactions in cells artificially expressing viral proteins. I will perform these experiments in the presence of reagents that inhibit protein degradation to allow detection of proteins that would have been degraded. I will use a flow-cytometry based assay to determine whether any candidate proteins are HCMV restriction factors. novel ARFs identified from this experiment will be characterised by further functional studies. I will also investigate the mechanisms in which HCMV degrades certain host proteins and will explore specifically why these proteins are targeted. These studies will be useful to further our understanding of virus-host interactions during HCMV infection as well as expand our knowledge of viral protein function.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFECTION
Award Title: Identification and characterisation of the molecular components associated with the human erythroid island niche in normal and abnormal erythropoiesis
Funder: Medical Research Council

Abstract: The transcription factor KLF1 is essential for the development and maturation of red blood cells (RBCs). A significant number of RBC disorders, including severe cases of anaemia, have been associated with KLF1 mutations. Research to date has focused on the intrinsic role of KFL1 in RBCs but  KLF1 is also expressed and plays an extrinsic role in macrophages associated with the erythroid island (EI) niche. We developed a novel in vitro model of the human EI niche using induced pluripotent stem cell derived macrophages and have generated a database of EI-associated KLF1 target genes that encode factors that can promote RBC maturation. We now plan to test secreted and membrane-associated EI factors for their ability to enhance the maturation of RBCs using recombinant proteins and synthetic biotinylated peptides captured in on streptavidin-coated plates. Patients heterozygous for the dominant negative KLF1-E325K mutation present with circulating nucleated cells and a profound anaemia. To determine how KLF1 deficiency in the EI niche contributes to their pathology we will differentiate macrophages from iPSCs carrying a tamoxifen inducible iE325K-ERT2 and iPSCs derived from CDA patients. We will test their ability to support the proliferation and maturation of RBCs and identify factors that are aberrantly expressed within the genetically defective niche using RNA sequencing, comparative proteomics and chromatin immunoprecipitation. Chimeric co-cultures will be used to define the intrinsic and extrinsic effects of the E325K mutation and we will define the erythroid- and macrophage-specific targets of KLF1-E325K. Knock-in and knock-out iPSCs will be generated using CRISPR/CAS9 technology to validate the function of these targets. The characterisation of factors associated with the EI niche will impact on the treatment of anaemia, by identifying novel drug targets and designing optimised protocols for the production of therapeutic RBCs from limitless sources such as iPSCs.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: BLOOD
Award Title: Identification of novel mechanisms of fetal-haemoglobin induction by common genetic variation in patients with sickle cell disease
Funder: Medical Research Council

Abstract: Our project aims to dissect quantitative trait loci (QTL) for the variable persistence of fetal haemoglobin (HbF) in patients with sickle cell disease (SCD). The HbF trait is clinically important: its variable expression contributes significantly to differences in disease severity.  Our research strategy is three-pronged: starting with genetic fine-mapping in four ethnically-diverse patient populations and a total of >3,000 patients, we will move on to functional studies in primary erythroid cells derived from individuals carrying specific variant haplotypes and will finally focus our observations by investigating human erythroid cells lines where individual genetic variants have been introduced through genome editing. Our main goals are (1) to identify novel molecular mechanisms by which common genetic variants at the HbF QTLs BCL11A and HBS1L-MYB affect pathways for the regulation of HbF; (2) to identify at least two novel causal SNPs driving the set of subloci occupying these QTLs and to weave those and robust sentinel SNPs into a universally-applicable polygenic score for the prediction of fetal haemoglobin and, ultimately, disease severity. (3) Our final goal is to help build research capacity in Africa: our collaborators in Tanzania and Nigeria will not only provide patients cohorts, but will also send trainees (one of them a post doc) to take charge of the genome-wide SNP data created for their patients, building a sustainable resource for future research. The post doc will investigate functional effects of key variants at 2 subloci by testing for changes in transcription factor binding (EMSA, ChIP), chromosome conformation (4C-seq) and gene expression, including HbF production. Novel pathways identified by our work are intended to ultimately lead to the development of affordable treatments of this devastating condition that each year causes thousands of childhood deaths in Sub-Saharan Africa.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: BLOOD
Award Title: Identification, characterisation and therapeutic targeting of gene regulatory complexes and networks in leukaemic stem cells.
Funder: Wellcome Trust

Abstract: Transcription factor (TF) networks are cardinally dysregulated in Acute Myeloid Leukaemia (AML), with many of these dysregulated TFs known to have developmental and homeostatic roles in normal haematopoiesis. I will focus on the E-twenty six (ETS) TF Pu.1 that is known to play an important role in myeloid and lymphoid development. Conventionally, Pu.1 is better known as a tumour suppressor during AML development but, more recent studies within the Huntly Lab have suggested an alternative role for Pu.1 in the maintenance of AML. I will be using an Npm1c/Flt3-ITD double-mutant mouse model, which recapitulates AML, to study Pu.1 in relevant leukaemic cell populations. I propose to study Pu.1 using chromatin-related genomic and proteomic techniques and will integrate these with gene expression analyses across normal-, early AML- and late AML-derived cell types. I will then aim to corroborating my findings from murine systems in AML patient samples. An understanding of changes in gene expression and the 3D chromatin structure caused by the binding of PU.1 and/or its interactors will unveil novel mechanisms of transcriptional regulation in the AML setting. Looking into the future, the combination of these experimental approaches may enable the development of therapeutics to specifically target PU.1-associated pathways AML.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Identify and rescue dysfunctional memory processes in mouse models of Alzheimer’s disease
Funder: Alzheimer's Research UK

Abstract: Cognitive dysfunction comprises a key symptom in AD in humans, it is important to develop a sensitive behavioural paradigm in mice that mimics our everyday experiences and allows characterisation of normal and abnormal memory processes in detail. This will strength the use of genetic mouse models as a vital platform for understanding and developing treatment for Alzheimer’s disease. Our rodent appetitive delayed-matching-to-place task simulates our daily experience of spatial memory updating, provides measurements to dissociate different components of memory processing, and sensitively shows memory decline at an early stage of normal ageing. This project aims to use this task to identify memory dysfunction in a newly developed APP knock-in mice model that overcomes shortcomings in the previous transgenic AD models. It will examine if memory retrieval is impaired in these knock-in mice; it will verify if the impaired function can be rescued by optogenetically reactivating the memory cells or by upregulating neurotransmission through receptors involved in memory retrieval; it will depict the relationship between memory cells and synaptic changes in the AD mice. Together, this project will advance our understanding of what memory processes are critically affected in AD mice and provide new targets for treating the memory impairment.

Lay Abstract: Cognitive dysfunction comprises a key symptom in AD in humans, it is important to develop a sensitive behavioural paradigm in mice that mimics our everyday experiences and allows characterisation of normal and abnormal memory processes in detail. This will strength the use of genetic mouse models as a vital platform for understanding and developing treatment for Alzheimer’s disease. Our rodent appetitive delayed-matching-to-place task simulates our daily experience of spatial memory updating, provides measurements to dissociate different components of memory processing, and sensitively shows memory decline at an early stage of normal ageing. This project aims to use this task to identify memory dysfunction in a newly developed APP knock-in mice model that overcomes shortcomings in the previous transgenic AD models. It will examine if memory retrieval is impaired in these knock-in mice; it will verify if the impaired function can be rescued by optogenetically reactivating the memory cells or by upregulating neurotransmission through receptors involved in memory retrieval; it will depict the relationship between memory cells and synaptic changes in the AD mice. Together, this project will advance our understanding of what memory processes are critically affected in AD mice and provide new targets for treating the memory impairment.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: Identifying and validating predictive Biomarkers in advanced oEsophageal adenocarcinoma – a springboard to REAListic medicine (BE-REAL).
Funder: Chief Scientist Office, Scotland

Abstract: Oesophageal adenocarcinoma (OAC) commonly presents at an advanced and thus incurable stage. Within the UK, Scotland has the highest incidence (972 cases/100,000 people in 2017). Chemotherapy is the main treatment, with side effects a significant feature. Side effects reduce quality of life and mean not all patients can receive chemotherapy. There is no accurate way to predict who will get side effects. Despite treatment, most patients will die within 12 months of diagnosis. There are a small group of patients (~10%) with long-term control and therefore improved survival and quality of life. The reason for this is unknown. If a reason for this sensitivity to chemotherapy can be found, it may allow a reduction in chemotherapy dose with subsequent reduction in side effects, improvement in quality of life and treatment of more patients. Previous research suggests the reason may lie in how the cancer repairs itself. I want to investigate this on a bigger scale, using existing samples from a trial in older, frailer patients with OAC. I want to develop a way to predict side effects and identify a test, after diagnosis, to enable a more individual treatment decision that will improve patient quality of life and reduce toxicity


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: CANCER AND NEOPLASMS
Award Title: Identifying disease promoting macrophages  and tissue-identity in endometriosis
Funder: Medical Research Council

Abstract: Endometriosis is a chronic inflammatory condition associated with debilitating pelvic pain and/or infertility that affects 176 million women worldwide. It is defined by the presence of endometrial-like tissue ('lesions') outside the uterus, commonly in the pelvic cavity. Treatments for endometriosis are limited and recurrence rates are high. There is an unmet need for new therapies. Macrophages are present at high densities in lesions and play a vital role in the pathophysiology of endometriosis by regulating lesion growth, vascularisation, neurogenesis and pain generation. In cancers, macrophages with different origins exist side-by-side.  'Tissue-resident' macrophages become educated by the tumour and promote disease whilst infiltrating 'monocyte-derived' macrophages act as innocent bystanders. We do not know if different subsets of macrophages exist in endometriosis, or if a subset promotes disease. Our preliminary data indicates that lesion-resident macrophages have multiple origins e.g. endometrium, peritoneum and circulating monocytes. We also have evidence that significant phenotype heterogeneity exists amongst lesion-resident macrophages.  We aim to identify which macrophages drive endometriosis and how the lesion educates 'pro-disease' macrophages using our in-house endometriosis mouse model with validation in patient biopsies. The identification of 'pro-disease' macrophages in endometriosis could inform the design of a therapy targeting pathogenic macrophages whilst leaving those critical for normal tissue function intact. Our objectives are to: 1. Determine phenotype diversity amongst endometriosis macrophages using scRNA-Seq 2. Use lineage tracing to determine ontogeny and fate of lesion-resident macrophages  3. Use targeted depletion strategies combined with imaging of lesions to determine which population drives disease 4. Identify lesion 'tissue-identity' signals required for macrophage recruitment/ differentiation using antibody arrays


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: REPRODUCTIVE HEALTH AND CHILDBIRTH
Award Title: Identifying novel neuro-computational treatment targets for mood instability
Funder: Medical Research Council

Abstract: Our mood could be the single most important determinant of life satisfaction, affecting all areas of our functioning and the actions we take in daily life. Clinically, mood instability is a highly debilitating feature of many psychiatric disorders, especially bipolar disorder, and is linked to risky and often harmful behaviours. This year, a commission for improving psychological treatments urged a return to basic mechanistic processes, which historically yielded many significant advances in evidence-based treatment but have unfortunately been largely ignored in recent research and treatment. The computational psychiatry approach is a promising and rigorous means of recapitulating symptoms into cognitive, behavioural and neurobiological processes. I will use this interdisciplinary approach to characterise the two-way relationship between mood instability and decision-making in bipolar disorder. Specifically, I will test a recent neuro-computational model in which elevated mood leads potential rewards to be perceived as bigger than they are, potentially leading to risk-taking behavior and further escalation in mood. I will use experimental tasks that manipulate mood states and model the resulting impact of mood on behaviour. By remotely deploying these tasks through a smartphone app, I will test whether model parameters from these tasks can track the trajectory of patients' mood instability in daily life.  I will combine lab- and smartphone-based measures of mood instability with functional MRI to characterise the neural circuits that mediate the mood bias on reward perception. Finally, testing the translational potential of this approach, I will evaluate whether this mood-on-reward-perception bias and fluctuations in the underlying neural signals can be reduced by mood regulation strategies. Taken together, this work will deliver a refined mechanistic understanding of mood instability that will provide a direct pathway for novel psychological intervention


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health Categories: MENTAL HEALTH
Award Title: Identifying the genetic architecture of brain health and disease in the presence of heterogeneity and multi-morbidity
Funder: Medical Research Council

Abstract: Alzheimer's disease and other forms of dementia are known to be highly complex conditions; phenotypes vary substantially across individuals, the majority of individuals have multiple chronic health conditions, and a wide range of genetic and lifestyle factors have been implicated in disease risk. However, the contribution and interaction of different mechanisms to produce distinct forms of Alzheimer's disease is not well understood. A complete understanding of how genetics, multi-morbidity and lifestyle factors give rise to heterogeneity in disease phenotype is crucial for developing targeted multi-faceted treatments and lifestyle interventions, as well as for identifying who they will benefit. In this fellowship I propose to develop new statistical approaches that can identify clusters of individuals with common disease trajectories and characterise how genetic factors and co-morbidities alter disease progression patterns. I propose to develop methods that can provide improved statistical power for detecting associations by (i) using machine-learning to bring together subjects at different disease stages to characterise heterogeneous trajectories across the full disease time course, enabling early stage subjects to be assigned to a subgroup trajectory; (ii) developing techniques that can cluster imaging, genetic and multi-morbidity information, particularly by jointly leveraging the structure of genetic and phenotypic information in combination. I will apply these techniques to provide new insights into variability in trajectories of the two most common forms of dementia, Alzheimer's disease and Parkinson's disease, and aging, which is the biggest risk factor for dementia and a key confound to distinguishing dementia at early disease stages. I will then test whether these imaging genetics profiles of health and disease can be used to screen for Alzheimer's disease and Parkinson's disease in population studies.


Research Activity Codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health Categories: NEUROLOGICAL