NIHRDataInsights/HRCSData huggingface dataset:
Title: Molecular mechanisms controlling peptide selection for immune recognition
Funder: Wellcome Trust

Abstract: Peptide presentation on MHC-I molecules is central to mounting effective antiviral and antitumoral immune responses. However, we currently lack full insight regarding how peptides are selected onto these extremely polymorphic molecules. Following our discovery that TAPBPR is an MHC-I peptide editor which shapes the final antigen repertoire displayed for immune recognition, we have recently identified that polymorphism in MHC-I significantly impact on their ability to be edited by TAPBPR. Our findings question the concept that all MHC-I molecules undergo peptide selection via a largely identical manner. Our overarching aim is to gain insight into how polymorphisms in MHC-I influence the mechanism by which they gain peptide. We will focusing on three aspects: 1. What impact do polymorphisms in MHC-I and TAPBPR have on the molecular mechanism of peptide selection? 2. What is the specific biological function of TAPBPR? 3. Can further molecular dissection of the presentation pathway reveal new insight into MHC-I biology and novel therapeutic targets? This work will enable deeper insight into how peptides are selected onto MHC-I. It will help uncover why specific MHC-I alleles are associated with particular disease. Furthermore, it will help in the development our novel TAPBPR-based therapeutics and maximise their full potential in cancer immunotherapy.

Lay abstract: MHC molecules present small fragments of proteins from within cells to alert the immune system to infection and cellular damage. Recently, we discovered a new accessory protein, called TAPBPR, helps select the peptides presented for immunological surveillance. However, MHC molecules vary incredibly from person to person. This affects the ability of TAPBPR to work efficiently. We do not know the consequence this has yet on how individuals respond to infections and cancer. We will explore how changes in both MHC molecules and TAPBPR affects the peptides presented to the immune system. We will explore exactly what TAPBPR does and how it works. We are all different when it comes to MHC and my laboratory are uncovering new layers of immunological individuality and complexity that has not been explored yet. This work will help us understand the role of MHC molecules in disease and develop new treatments for cancer.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM
Title: MICA: The Newcastle Proximity Laboratory
Funder: Engineering and Physical Sciences Research Council

Abstract: Building on strengths in discovery science we will provide world-class training to a new generation of molecular pathologists, producing a step-change in the delivery of precision medicine. We will prioritise the development of in vitro diagnostics in chronic and rare diseases, ensuring pull-through to industry and clinical practice using well established links with the Newcastle NIHR DEC and our recent Proximity to Discovery Award. Our technical focus will be solving challenges posed by multiparameter analysis of microbiopsies, working with engineers in the Newcastle nanoLAB and Diagnostics & Therapeutic Technologies group. We will develop methods for the data analysis, interpretation and integration of results into clinically useful formats through collaboration with our Interdisciplinary Computing & Complex BioSystems research group and provide high quality samples for research partners using our established Biobank. Our main base will be in an NHS Pathology Department, ensuring close interaction with clinical pathologists. Building on experience gained with developing our Wellcome Trust Translational Medicine & Therapeutics Programme we will extend our e-learning Masters in Translational Medicine & Therapeutics to include a strand on Molecular Pathology, linked to the development of intercalated degrees for medical students to promote capacity building. We shall sit within infrastructure at Newcastle that includes the NIHR BRC in Ageing & Age-Related Chronic Disease, the NIHR BRU in Lewy Body Dementia, the MRC Centre for Brain Ageing & Vitality, the Wellcome Trust Centre for Mitochondrial Research, the MRC Centre for Neuromuscular Disease, an NIHR Bioresource in Rare Diseases and an NIHR Blood and Transplant Research Unit in Organ Donation & Transplantation. Programme Grant awards support research into stratified medicine and the biology of liver, musculoskeletal, neuromuscular diseases and cancer, ensuring a supply of novel approaches for further development.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM;ORAL AND GASTROINTESTINAL
Title: Chromatin control of environmental stress response
Funder: Medical Research Council

Abstract: Cells respond to environmental stress and toxins by mounting an adaptive stress response in order to survive stressful conditions. Transcriptional control is a major regulatory layer that determines the strength, the duration and persistence of cellular stress response. Transcription factors, chromatin modifications and non-coding RNA influence the transcriptional response to environmental stress. The molecular mechanisms by which chromatin exerts control over stress response is the main focus of the Unit programme. We aim to address the following questions: (i) Which cellular pathways sense environmental stress/ toxins and signal to the genome? (ii) How does chromatin interpret the information about cellular health and toxic exposure determining the transcriptional response to stress? (iii) How does the transcriptional response adapt cellular phenotypes to survive the stress? We study these three questions in the context of cellular exposure to environmental stress as well as small-molecule therapeutics in collaboration with pharmaceutical companies. Our approaches include genomics, single-cell transcriptomics, proteomics, chromatin biochemistry as well as genome-wide screening to identify novel components of stress-response pathways. Discovery-driven global approaches in mammalian cells are further validated by in vitro reconstitution experiments and mouse genetic models. We aim to gain novel insights and mechanistic understanding of transcriptional response to environmental toxins. In addition, our research will shed light on unintended toxicological effects of therapeutics. With the approach of understanding molecular basis of toxic effects, our research will suggest ways of mitigating with stress and toxicity.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS;INJURIES AND ACCIDENTS
Title: Post-operative exercise interventions on the physical and mental health of people with colorectal cancer receiving adjuvant therapy
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Colorectal cancer is the third most common cancer diagnosed worldwide with an estimated 1.36 million cases diagnosed in 2012 (Ferlay, J et al., 2016). Colorectal cancer survival rates are increasing due to improvements in treatments and early detection (Spence, R et al. 2007). A considerable proportion of patients will go on to become long-term survivors. However, reductions in cardiorespiratory fitness, skeletal muscle mass and an increase in adipose tissue present a series of adverse comorbidities for colorectal cancer survivors that can severely impair prognosis following treatment (Courneya et al.,1997). They also have the potential to develop second colorectal and non-colorectal cancers, comorbid conditions, short term side effects and long-term effects of treatment (Denlinger,C. & Engstrom,P, 2011). As the number of colorectal cancer survivors increase there is a need to develop effective interventions which aid physical and psychological recovery, help alleviate treatment side effects, increase survival and decrease cancer recurrence. Traditionally, cancer patients have been advised to rest and avoid physical activity; however in recent years, research has challenged this recommendation (ACSM, 2010). Exercise interventions are conventionally used in the rehabilitation and management of various chronic conditions and may have the potential to be an effective component of the colorectal cancer control continuum. However, there is a requirement for a greater understanding amongst decision makers, clincians and patients of the potential benefits of exercise training on physical and mental health of colorectal cancer patients. Objective: This proposed systematic review will evaluate the effect of exercise interventions on the physical and mental health of individuals who have undergone surgical intervention for colorectal cancer and are receiving adjuvant therapy. Types of study/interventions and comparisons to be made: Randomised control trials and clinical control trials that evaluate exercise and physical activity interventions in various settings (home, community and hospital based exercise; group and individualised exercise) with varying frequency, intensity, volume and mode will be included in the review. Comparison groups will include standard care, control group (no structured prescription of exercise), another intervention or no exercise. Primary outcome: to assess the effectiveness of post-operative exercise interventions on the physical and mental health of people with stage I-III colorectal cancer receiving adjuvant therapy using subjective measures* of exercise capacity, weight and biomarkers for health and objective measures* of physical function, cancer related fatigue, overall quality of life, and anxiety and depression.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS;MENTAL HEALTH
Title: The causal role of the nutritionally regulated insulin-like growth factor system in prostate cancer: Mendelian randomization study
Funder: World Cancer Research Fund

Abstract: Background: Hormones that regulate how tall we grow and the normal development of our organs in early life circulate in high concentrations in our bodies. Levels of these hormones vary considerably (due to differences in our genetic make-up, diet and other reasons), and partly explain differences in height between individuals. However, in adulthood, after we have finished growing, people who have raised levels of these hormones seem to have an increased risk of cancer, including prostate cancer. The possible reasons for this finding, which has been shown in many studies, are unclear and the picture is currently confusing. Some people assume that the finding occurs because high levels of these hormones cause imbalances in the normal growth and production of cells and tissues in adulthood, which ultimately leads to the development of abnormal cells that become cancers. Others argue that the hormones don't cause cancers to develop, but high levels can cause those that have already started growing to become more aggressive/serious and to spread around the body. Another explanation is that the cancers themselves produce these hormones. Thus, raised levels of these hormones may not cause cancer or its progression, but are an indication that a cancer may be present. The final explanation is that these findings are nothing to do with the hormones, but are due to other factors that are in some way related to them. Aims & Goals: Our research aims to understand why men with prostate cancer appear to have raised growth-related hormone levels. How it will be done: We will do this by assessing whether men with a genetic make-up that causes a rise in these hormones also have an increased risk of prostate cancer developing or progressing, or whether raised hormone levels are due to the presence of tumour. We will look at hormone levels in 2000 men with prostate cancer and 2000 healthy men. Potential impact: The research is important, because if growth-related hormones cause prostate cancer or its progression, then we could potentially design treatments that lower hormone levels in order to prevent the initiation or progression of prostate cancer. Nutritional interventions may be relatively straightforward to develop as we already know a number of the nutritional determinants (e.g. milk) of growth-related hormones. If, instead, it is the cancers that cause a rise in the levels of these hormones, then we could use this information to develop clinical blood tests to diagnose the presence and aggressiveness of prostate cancer and to monitor the response of prostate cancers to treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE
Title: A toolkit for tyrosine kinase signalling network analysis.
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Tyrosine kinases (TKs) control multiple essential physiological processes including multi-cellular development and metabolic homeostasis. Deregulation of TKs and their associated downstream signalling cascades are key drivers in debilitating diseases such as diabetes and cancer. Consequently, the ability to accurately profile TK signalling events at a systems level is of considerable interest. Here we seek to develop a prototype Toolkit which measures TK signalling networks into a contract-based service and explore the further development of the technology as "kit"-based profiling products for non-specialist users. We envisage that this commercial service will be of interest to a broad range of investigators who wish to profile cellular signalling in multiple biological contexts. Furthermore, the development of a kit-based product will enable non-specialist investigators to perform such experiments using standard equipment found within proteomic core facilities.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE
Title: The role of 14-3-3 proteins in cellular responses to growth factors and nutrients
Funder: Medical Research Council

Abstract: How a few intracellular signalling pathways, including PI 3-kinase/PKB, MAPK/p90RSK and AMPK, stimulate wide-ranging changes in cellular behaviours is a fascinating problem, made all the more pressing because these pathways are deregulated in diabetes and cancers, while AMPK mediates beneficial responses to exercise and the anti-diabetic drug metformin. Using 14-3-3 capture and release, combined with differential proteomics, we are discovering how the PI 3-kinase/PKB, MAPK/p90RSK, and AMPK signalling pathways stimulate the phosphorylation and binding to 14-3-3s of large, overlapping subsets of proteins. For example, the Rab GTPase activating protein AS160 is phosphorylated and binds to 14-3-3s in response to insulin, while the related TBC1D1 binds to 14-3-3s in response to AMPK activators. Our biochemical and transgenic mouse experiments suggest that the relative sensitivity of glucose uptake to insulin and/or exercise in different tissues may reflect the different tissue distributions of AS160 and TBC1D1. Biochemical dissection of other target proteins is revealing new mechanisms to explain how insulin, growth factors and nutrients regulate vesicle trafficking, signalling, mitochondrial biogenesis and gene expression. One exciting new project stems from the discovery that EGF stimulates the MAPK/p90RSK-mediated phosphorylation and 14-3-3-binding of multiple components of a transcriptional network implicated in spinocerebellar ataxias, dopaminergic disorders and Ewings family sarcomas. These findings suggest a new hypothesis about how altered growth factor control of neural crest differentiation might contribute to these diseases, and suggest 14-3-3s as therapeutic targets for tumours. Another ambitious goal of our 14-3-3-phosphoproteomics approaches is to identify a core list of proteins that have distinctive signalling signatures and whose 14-3-3-binding status could be used as biomarkers to report on which signalling pathways are active in healthy and disease tissues, and how they respond to drugs.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE
Title: Understanding degradation of heparan sulphate with implications for disease.
Funder: Wellcome Trust

Abstract: The human body comprises around ten trillion cells, which together perform every function we require to sustain life. Communication between cells is vital and an important role is played by the region between cells, the extracellular matrix, which is filled with proteins and sugar chains. The sugar chains consist of repeating units of sugars and possess modifications; one example is called heparan sulphate (HS). I am interested in how the enzymes, proteins that catalyse biological reactions, res ponsible for breaking down HS operate, particularly in relation to how their malfunction is implicated in diseases. One enzyme becomes over-active in aggressive forms of cancer, which aids destruction of the extracellular matrix and allows tumour invasion. Inhibition of this enzyme may provide a way to slow cancer progression. Other enzymes, located in a compartment in the cell called the lysosome, completely break-down HS into its components. A genetic error causes them to become unstable and n ot function, meaning HS fragments accumulate, leading to a lysosomal storage disorder. Administering a small amount of enzyme inhibitor can stabilise the enzyme and allow it to function. Understanding the enzymes involved in the break-down of HS should enable development of therapeutics for cancer or lysosomal storage disorders.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE
Title: Co-producing with the local community an action plan to reduce consumption of high fat, sugar and salt foods in Newham.
Funder: Medical Research Council

Abstract: Background: Newham has a high prevalence of diabetes and obesity; these conditions cause a high burden on primary and secondary health services, and are also associated with worse outcomes from Covid-19. Newham is ethnically diverse with 73% of its population coming from an ethnic minority background. This is particularly relevant as diabetes rates are three times higher in Black African and Black Caribbean groups, and six times higher in South Asian groups. Levels of deprivation are also high, with the borough being within the 20% most deprived areas in England. Although there are existing services to prevent diabetes and encourage weight-loss, these are nationally devised programmes that are not well-suited for this low-income, ethnically diverse population. This is potentially leading to the widening of health inequalities in areas such as Newham. Proposed methods: We will use co-production methods to develop the job description and training manuals needed for a local Food Champions intervention to reduce the consumption of high fat, sugar and salt foods. We will conduct a rapid realist review of Food Champion projects and construct stakeholder maps of the Newham food system. We will work with community groups from eight areas of Newham, plus 2 more groups recruited from the whole of Newham to co-produce causal loop diagrams, or systems maps, of the factors affecting poor diet in Newham. Each group will be asked to identify suitable areas for action within the system, with guidance from a facilitator. This information will be used by an intervention development group consisting of researchers and local project partners. This group will use the information from the workshops to construct a Theory of Change model to identify what aspects of the Newham food system local Food Champions should act on and what training would be needed. Draft intervention training manuals will then be drafted.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;ORAL AND GASTROINTESTINAL;STROKE
Title: Fundamental mechanisms controlling human energy homeostasis
Funder: Wellcome Trust

Abstract: Obesity and associated diseases such as type 2 diabetes, cardiovascular disease and some cancers represent a significant health burden. My overall aim is to identify new therapeutic strategies for severe obesity. Using extensive genetic and clinical data on unique cohorts of individuals at both extremes of the weight distribution (severe obesity and thinness), we will comprehensively map the molecular networks that maintain energy homeostasis and their disruption in disorders of weight regulation. Building on our previous work, we will focus on dissecting cellular mechanisms that converge on leptin-melanocortin signalling using human stem-cell derived hypothalamic neurons. In human studies, we will characterise the effects of specific pathways on eating behaviour, energy expenditure and substrate utilisation. By uncovering the fundamental mechanisms that control human energy homeostasis, our goal is to identify and validate control points that can be targeted to improve outcomes in obesity associated diseases.

Lay abstract: We are interested in finding out why some people gain weight more easily than others, so that we can find treatments for conditions such as diabetes. Our aim is to find the genes that contribute to weight problems and the genes that allow some people to stay thin. We have identified quite a few genes – interestingly, they all act on the same pathway. We are now trying to piece together some of the finer details about this pathway. We predict that there will be groups of genes that work together to control our eating patterns and the way we burn calories. We want to test the new genes we discover in nerve cells that can be made from stem cells, which give us a window into how the brain works. A key part of our research is that we invite people to contribute to clinical studies to help us find out how certain genes act by measuring various hormones and metabolism in new state-of-the-art facilities. Our overall aim is to make a major contribution to the design of treatments that will benefit people who really struggle with their weight and reduce the burden of conditions such as diabetes.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;STROKE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: Combining randomised controlled trials and population-based ‘omic research: an exploration of how adiposity causes disease
Funder: Wellcome Trust

Abstract: Fatness is linked to increased risk of diseases including type 2 diabetes, cardiovascular disease, cancer and some infectious diseases. However, the reasons for these links are not fully understood. Metabolites are small molecules in the blood that can be measured and potentially help to explain links between differences in body composition and disease outcomes. I will use metabolite data from blood samples from patients who have undergone a weight loss intervention (bariatric surgery or a lifestyle intervention) to try to unpick the relationship between fatness and disease. Metabolites are linked to a person’s genes, so I will also use genetic data from population-based studies to support my findings using alternative methods. This study will increase understanding of the pathways between fatness and disease at a molecular level. In addition, findings from this study may help to identify who will benefit most from different weight loss interventions, or even identify potential pathways that can be targeted to help patients with obesity improve their health.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;STROKE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL