NIHRDataInsights/HRCSData huggingface dataset:
Title: PET Methodology
Funder: Medical Research Council

Abstract: In the next five years we want to progress the set of technologies that PET Methodology has built at Hammersmith for the field in the past 20 years with the aim of increasing PET accuracy and expand its applications to provide ever more useful end-points for diagnostic use, clinical research and drug development. We will support the introduction of new tracers in the Unit (e.g. 11C-Ro-154513, 11CCUMI, 11C-CNS-5161, 11C-MePPEP) developing tailored quantitative methodologies. We will employ novel modeling approaches (e.g. generalized reference region models) to simplify,without loss of precision, the use of PET in research and drug development. To support the imaging work in Neurodegeneration, we will expand our methodological toolbox on imaging inflammation developing quantification methods for the new generation of high affinity TSPO radiotracers such as 11C-PBR28 and 18F-FEPPA. We will be also looking at translational models of senescence to identify aging microglia phenotypes and their markers. To support the work in Psychiatric disorders, we will develop methodologies able to quantify the dynamics of large neuronal ensembles from fMRI time-courses looking both at local and regional determinants using concepts from network analysis and statistical physics. We will then use these endpoints in combined fMRI/PET study designs to measure the relationship between receptor densities/endogenous neurotransmitters levels (e.g. using dopaminergic tracers such as 18F-FDOPA, 11C-Raclopride, 11C-FLB457 or cannabinoid tracers such as 11C-CB1) and neuronal dynamics. In Cancer, we will work on two paths. On one side we will research novel quantification methodologies for radiotracers used in clinical studies at the Unit (18FFluorothymidine, 18F- AH111585 e 18CCholine) to model their complex and heterogeneous kinetic behavior in tumor cells. In parallel, we will be developing computer aided strategies able to use features of functional (PET) and structural (CT) images to automatically detect tumors in functional or multimodal studies. Our work on Genomics will continue with focus on the epigenetics of brain disorders (Huntington‘s and Parkinson‘s disease, Schizophrenia and bipolar disorders) using computational models applied to microarray data for exploration and guide for further genomic (ChIP-Seq) studies.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: MENTAL HEALTH;INFLAMMATORY AND IMMUNE SYSTEM;CANCER AND NEOPLASMS
Title: Mode-Of-Action Ecotoxicology of Pharmaceuticals
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Current testing of human pharmaceuticals for possible environmental effects is widely accepted to be inadequate. It is proposed that fish, being very similar to mammals at the biochemical and molecular levels, will respond to pharmaceuticals in the same way that humans do; that is, the mode of action in humans is likely to be the main mode of action in fish. Further, it is hypothesised that to exert an effect, the blood concentration in fish will need to be similar to that in patients taking the drugs. This has recently been shown to be true for beta-blockers, but its wider applicability to other classes of pharmaceuticals is unknown. This proposal is for a 'proof of principle' project, which will study representative drugs from four different classes of pharmaceutical (COX inhibitors, SSRIs, ACE inhibitors, and synthetic glucocorticoids). Zebrafish will be exposed to ibuprofen, fluoxetine, quinapril and beclomethasone at concentrations sufficient to establish therapeutic plasma levels, which will be confirmed by LC/MS/MS measurements. Endpoints relevant to their modes of action in humans will be measured. In order to establish that effects are only seen at therapeutic concentrations, fish will also be exposed to a concentration of each drug 100-fold less than that required for therapeutic plasma levels. If, as anticipated, the results support the so called 'read across' hypothesis from mammals to fish, they would provide a very strong driver for the development of an efficient and effective testing strategy for pharmaceuticals, and refinement of the current regulatory testing, which is designed for toxic chemicals, and not those with known biological actions such as pharmaceuticals.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH;INFLAMMATORY AND IMMUNE SYSTEM;CARDIOVASCULAR
Title: How does chronic liver disease in infancy and childhood alter brain maturation?
Funder: Medical Research Council

Abstract: Design: exploratory study with recruitment of 72 adolescents from our clinical service to acquire a brain MRI and characterise their cognitive and behavioural phenotype. Methods i) MRI overview: Because different measures are sensitive to distinct neurodevelopmental processes, with specific spatial and temporal patterns of development over childhood and adolescence, structural [volumetric and microstructure (DTI)], functional MRI and Magnetic Resonance Spectroscopy (MRS) for brain chemistry will be acquired. First-pass analyses will examine the extent to which there are volumetric and microstructural differences between adolescents with chronic liver disease and the normative data obtained from the reference cohort; because these indices have already been shown to predict cognitive and adaptive outcomes. ii) Cognitive and behavioural measures: These will include the Vineland Adaptive Behaviour Scales and the Wechsler Intelligence Scale for Children (WISC) as primary measures for first pass analyses. Standardized and validated categorical diagnostic outcomes (e.g. ADHD, ASD, Anxiety and Mood disorders), clinical and continuous outcome measures (neurodevelopmental and psychiatric traits) including socio-emotional, intellectual and executive skills (age-appropriate) will also be recorded to support secondary analyses. We will examine whether individual deviations in brain maturation are correlated with IQ and adaptive outcomes measures initially, before moving to investigate finer-grained outcomes. iii) Mechanistic variables: including liver function indices, markers of pubertal development and inflammatory status. Our first pass analyses will examine whether individual deviations in brain maturation are correlated with validated indices of liver disease and/or pro-inflammatory cytokines. For secondary analysis, detailed indices of liver function (biochemistry, haematological, hormonal), ultrasound scan and fibroscan will be accessed for analysis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;7.1 INDIVIDUAL CARE NEEDS
Health categories: MENTAL HEALTH;INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Epigenetic signatures of inflammation in relation to brain structure and connectivity across the lifecourse
Funder: Wellcome Trust

Abstract: How does chronic inflammation affect brain structure and connectivity as we grow older, and what aspects of our lifestyle influence this? We know that inflammation affects the function and integrity of the brain, with adverse outcomes in both development and older-age. Chronic, low grade inflammation is usually assessed by measuring the levels of various proteins in the blood, yet these measures provide only a snapshot of inflammatory exposure. A more reliable indicator may arise from DNA methylation, an epigenetic modification that is influenced by both genes and environment, and is involved in the regulation of gene expression. Using three distinct cohorts (age ranging from newborn (<1y) to older adults ~70-80y), we will investigate DNAm estimates of inflammation alongside various lifestyle factors and how these associate with specific aspects of brain structure and connectivity. In generating robust DNAm signatures of brain health and decline, we may expose novel pathways or therapeutic targets for inflammation, as well as new insights into how our lifestyle shapes our brain as we age – highlighting which risk factors to address to promote brain health.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: How does insulin in the bloodstream trigger dephosphorylation of regulatory proteins of cell morphology and dopamine synthesis in the brain?
Funder: Diabetes UK

Abstract: Diabetes is strongly associated with depression and cognitive decline, but the molecular reasons are unknown. Therefore, we were intrigued to see a striking dephosphorylation of many proteins in response to insulin and in a fasting state (refed before) in mice. The regulated proteins were purified and included regulators of cell morphology (MAPT(tau), srGAP3, MARK3, MARK4), dopamine synthesis (tyrosine hydroxylase), and FAM122A that interacts with protein phosphatase PP2A. Interestingly, these proteins are linked to neurological disorders (e.g. MAPT(tau) is hyperphosphorylated in Alzheimer’s); all belong to paralogue families that evolved at the invertebrate-vertebrate transition; all are targets of cAMP-PKA signalling; and we also identified these proteins in a separate project to define the 14-3-3-binding phosphoproteome of melanoma cells. Further findings are inconsistent with the observed dephosphorylations being mediated by active insulin signalling. Therefore, to deduce the relevant mechanisms we will complete the identification of dephosphorylated target proteins, (de)phosphorylated residues and relevant protein kinases. The ‘signalling signature’ of each phosphorylation will be defined in terms of its responsiveness to stimuli/inhibitor combinations. Further work will depend on whether or not these experiments support the hypotheses that the observed dephosphorylations are due to inhibition of insulin and/or dopamine-cAMP-PKA signalling.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;METABOLIC AND ENDOCRINE
Title: TRUMP: A Trusted Mobile Platform for the Self-Management of Chronic Illness in Rural Areas
Funder: Engineering and Physical Sciences Research Council

Abstract: Chronic diseases are now the leading causes of death in both developing and developed countries. Such conditions include diabetes, asthma, arthritis, heart failure, COPD, dementia and a range of disabling psychological conditions such as depression. In the UK the cost of care of people with chronic conditions consumes the majority of health and social care resources, for example, accounting for over 80% of GP consultations. While the UK and India have very different practices and structures for healthcare delivery, the effective management of chronic illness is a priority for both countries. Patients in rural areas, however, present particular challenges that neither country's healthcare systems are well configured to address. This issue is particularly relevant to India with 71% of the population in rural areas. While less than 1 in 5 of the UK population are rural dwellers, large parts of the country are sparsely populated; for example in Scotland, 29% of the population live in rural areas. Rural healthcare inequality in both countries arises from a number of factors, including transport costs and the inaccessibility of specialist services. The goal of the TRUMP project is to explore the potential of mobile technologies in the development of a platform to support chronic disease management by simultaneously considering the needs of rural areas of India and the UK. Trust in such systems is vital if they are be accepted by patients and health workers alike, and this issue will form a central part of the development of the platform. Two common chronic conditions, diabetes and depression, have been chosen as exemplars for the development of the platform and its evaluation. TRUMP is a multidisciplinary project involving academic researchers from the UK and India, together with partner organisations drawn from the business and community sectors. Working together, this team will: perform a detailed analysis of the healthcare context, design sustainable technology solutions compatible with local and national healthcare policies; incorporate existing proven chronic management programmes and training. This implies support for novel patient record systems, mechanisms for tracking the patient (symptoms and behaviour), as well as patient awareness of self-management.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MENTAL HEALTH;METABOLIC AND ENDOCRINE
Title: Epidemiological studies of human transgenerational responses (TGR) to paternal and ancestral exposure
Funder: Medical Research Council

Abstract: There is growing evidence from animal and human studies that sperm carry information about the paternal and ancestral environment that influences the health of the next generation(s). Understanding these transgenerational responses (TGR) is likely to bring substantial public health and medical benefits. This project builds on the results of an earlier collaboration between the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Overkalix cohort in Northern Sweden that provided clear evidence that sex-specific, male-line TGR exist in humans (Pembrey et al EJHG 2006;14:159). The Overkalix historical data shows associations between the food supply of the paternal grandfather in their early childhood with the mortality rate (and diabetic deaths) of their grandsons. It also demonstrates a similar association with early life exposures (from conception to 3 years) in the paternal grandmother with respect to her granddaughters. ALSPAC data shows that commencement of smoking before 11 years of age in the father is associated with higher body mass index in his future sons but not daughters mortality rate. A Taiwanese study on paternal betel nut chewing points to the metabolic syndrome as a TGR outcome in the father?s offspring. Many of these results mirror those found in animal experiments. This project will use ALSPAC data to test the fetal and childhood exposures of study parents to toxins such as cigarette smoking as a TGR trigger for features of the metabolic syndrome in study participants. The analysis will investigate previously observed sex differences in early childhood exposure sensitive periods as well as sex differences in offspring outcomes. In line with animal data, early life ?traumatic events? in study parents (death of a parent, divorce or separation) and paternal grandmother (onset of war) will be examined as a stressful TGR trigger in relation to behavioural and cognitive traits in the study participants. Features of the metabolic syndrome will also be included in these offspring outcomes to evaluate whether toxic and stressful TGR triggers result in a similar range of downstream outcomes or whether stressful triggers only lead to behavioural and cognitive effects in the offspring. Answers to these questions will help inform future molecular (epi)genetic studies investigating the molecular mechanisms underlying male-line TGR.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: MENTAL HEALTH;METABOLIC AND ENDOCRINE
Title: AMBROSIAC - A Menu for Brain Responses Opposing Stress-Induced Alterations in Cognition
Funder: Medical Research Council

Abstract: This proposal investigates how diet through stress-related mechanisms affects cognition across the lifespan using preclinical and clinical approaches. Particular focus will be on the influence of nutrition on increased susceptibility for stress-induced cognitive deficits in memory and executive functioning from adulthood to old age (aim 1) and the impact of a nutritional intervention on cognitive ability, stress vulnerability and stress perception (aim 2). Next, the molecular mechanisms by which targeted nutritional interventions can improve stress-induced vulnerabilities in cognition will be investigated using preclinical models (aim 3). Throughout the 3 aims, the gut microbiota will be investigated as a novel critical signalling mediator between nutritional intake, stress susceptibility and maintenance of cognitive health in ageing (using samples from aims 1, 2 and 3). Elucidating the cellular and molecular mechanisms and pathways through which nutrition can promote the resistance of neurons to insults and enhance mental fitness will help us to determine how best to modulate diet composition in order to attenuate stress vulnerability, reduce susceptibility to metabolic disorders, and ultimately promote brain health during healthy ageing.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: MENTAL HEALTH;METABOLIC AND ENDOCRINE
Title: Optimising recruitment for adults with learning disability and type 2 diabetes. The Quintet Recruitment Intervention (QRI)
Funder: Public Health Agency, NI

Abstract: The purpose of the study is to test whether the adults with learning disabilities who received the diabetes education programme have better health outcomes compared to those who do not receive the education programme regarding their knowledge, diets, physical activity, mood, weight, BP, cholesterol, and HbA1c. With the permission from the adults with learning disability, half will be randomly selected to receive the diabetes education programme, while the other adults with learning disabilities will continue with their usual diabetes care


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: MENTAL HEALTH;METABOLIC AND ENDOCRINE
Title: Applying a life course perspective to genetic risk perception for type 2 diabetes in British Bangladeshis and British Pakistanis
Funder: Wellcome Trust

Abstract: Research on the communication of genetic risk information for common conditions like type 2 diabetes (T2D) has largely focused on disease identification, prevention and management in older, White European populations. Much remains unknown about the use of genetic risk prediction tools in diverse ethnic and/or age groups—however, emerging work in South Asian populations suggest that such tools may have added benefits for the identification of younger people at risk of developing T2D. We are interested in applying a life course perspective to this research area to examine potential age differences in perceptions and beliefs surrounding T2D—including whether young people perceive unique benefits from acting on their genetic risk status. We will first synthesise currently available evidence on genetic risk communication and illness perceptions. Then, we will provide genetic risk information about T2D to a community-based cohort of British Bangladeshis and British Pakistanis in the UK—integrating the findings from our synthesis—to investigate any age differences in how people evaluate information and formulate ideas about their risk; and compare different formats of risk communication. This research will inform efforts addressing the potential of genetic risk communication for a population disproportionately affected by T2D—yet underrepresented in genetics research.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;METABOLIC AND ENDOCRINE
Title: Linking education and health data together to study relationships between various health factors and children's educational and health outcomes.
Funder: Medical Research Council

Abstract: Initial chronic conditions of interest are diabetes, epilepsy, asthma, ADHD, depression and skin disorders. These conditions can be identified via linkage of children's education records to the PIS prescribing database to provide information on prescription medications taken by children before and at the time of the school census. Disease severity will also be investigated through dose and type of medication. Other childhood risk factors of interest for poor educational outcomes include morbidity resulting in acute or psychiatric hospital admission, early life morbidity (e.g. neonatal admissions and poor early child development), birth outcomes (e.g. congenital anomalies), lifestyle (e.g. breastfed) and maternal antecedents (e.g. in utero drug exposure). Many of these factors are correlated and analyses will be done taking into account confounding factors. Additional linkages will be explored if necessary in order to uncover additional confounders.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: MENTAL HEALTH;METABOLIC AND ENDOCRINE;NEUROLOGICAL;RESPIRATORY;SKIN
Title: Is gestational diabetes associated with adverse maternal and child mental health outcomes?
Funder: Medical Research Council

Abstract: Background:gestational diabetes (GDM) is glucose intolerance with onset during pregnancy. It has a UK prevalence of between five and 10% and leads to adverse outcomes for mother and baby, including increased risk of type two diabetes (T2DM) in the mother and adverse child neuro-behavioural outcomes. Mental disorder is the most common morbidity of the perinatal period and is also associated with adverse child neuro-behavioural outcomes. There has been no research on how mental disorder influences future outcomes in mother and child in those with GDM. Objectives:to establish the extent to which GDM is associated with adverse maternal mental health outcomes and whether mental disorder in those with GDM is associated with subsequent development of T2DM and adverse child neuro-behavioural outcomes. Methods:Study 1a- systematic review and meta-analysis of prevalence and odds of all perinatal mental disorders in women with GDM. Studies 1b, 2 and 3 utilise the Born in Bradford cohort. Study 1b-risk for perinatal mental disorder in women with GDM will be assessed from a questionnaire about mental symptoms and diagnoses from primary care records. Mechanisms for the association will be explored including inflammation and behavioural factors. Study 2-future risk of T2DM in women with GDM and antenatal mental disorder will be investigated using primary care diagnoses of T2DM. Behavioural factors such as diet and physical activity will be explored as potential mechanisms. Study 3-neuro-behavioural outcomes of children whose mothers had GDM and antenatal mental disorder will be investigated using two measures of the child's development at ages four and seven. Maternal glycaemic control and persistence of mental disorder into the postnatal period will be explored as potential mechanisms. Potential benefit and impact:exploring the relationships between GDM and mental disorder and potential mechanisms for the associations will help inform tailoring of healthcare interventions


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH;METABOLIC AND ENDOCRINE;REPRODUCTIVE HEALTH AND CHILDBIRTH