NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Digital support for physical activity in rheumatoid arthritis (DASH-RA)
Funder: Versus Arthritis

Abstract: Physical activity is beneficial for people with rheumatoid arthritis and is a key non-pharmacological management strategy which directly impacts on quality of life. However, people with rheumatoid arthritis report barriers to taking part in physical activity and are often reluctant to participate for fear of symptom exacerbation. Traditionally, support to engage with physical activity has been provided through face-to-face behaviour change interventions but limitations with access have been identified.  Interventions using digital technology may address the limitations of face-to-face interventions and provide a more flexible support option. Research is required to establish the most usable, acceptable and effective ways to encourage long-term adherence to physical activity in people with rheumatoid arthritis via digital behaviour change interventions. Therefore, the aim of this studentship is to develop a prototype digital behaviour change intervention for people with rheumatoid arthritis, to facilitate sustained engagement with physical activity. This will be conducted across three work packages (WP):

WP1a: Survey to explore existing use of physical activity digital interventions for people with rheumatoid arthritis including content and evidence of engagement.

WP1b: Rapid review to identify existing research evidence relating to digital interventions for physical activity in rheumatoid arthritis.

WP2: Development of a prototype digital behaviour change intervention informed by behaviour change theory through an intervention mapping process and co-design workshop.

WP3: Investigation of the usability and acceptability of the prototype intervention through 12-week pilot and individual semi-structured interviews with 12-15 participants.

The outcome of the studentship will be a prototype digital behaviour change intervention for people with rheumatoid arthritis to facilitate and sustain engagement with physical activity. This intervention will be ready for feasibility testing and have preliminary evidence of how the intervention might work for different groups in different circumstances.


Research Activity Codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL;5.7 PHYSICAL
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Disability: Experiences and Perspectives from Zimbabwe’s Indigenous Doma people
Funder: The British Academy

Abstract: Disability literature is largely dominated by scholars and studies from the global North, and these studies are based on global North theories and concepts. This distorts the realities of people with disabilities in the global South as their voices remain on the fringes of disability discourses. The aim of this proposed ethnographic qualitative project is to shed light on disability in the global South by utilising the Indigenous Ubuntu philosophy. This study will be undertaken within the Doma communities in northern Zimbabwe through narrative interviews. Participants will include people with disabilities and their families, traditional leaders and other key stakeholders e.g., Disability organisations’ representatives. The significance of this project is that it seeks to challenge the global hegemonic discourses on disability by transforming the ways in which disability is understood. This project will ultimately contribute to both national and international policy making.


Research Activity Codes: 7.1 INDIVIDUAL CARE NEEDS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Discovering New Pathways of Preleukaemic Dysregulation from Single Cell Transcriptional and Chromatin Landscapes
Funder: Wellcome Trust

Abstract: Blood stem cells ensure the constant supply of new blood cells throughout a person’s lifetime.  The normal function of blood stem cells critically depends on the fine tuning of which genes should be active at any given time.  Moreover, a large number of leukaemias arise when this fine balance of gene activities is disturbed.  Through my research I want to answer the following questions:
 
  • What are the mechanisms which regulate gene activities to ensure normal blood stem cell function? 
  • Can we identify new strategies to treat leukaemia by reversing the disturbed balance of gene activities?
 
To answer these questions, I plan to use a combination of experimental and computational approaches, in order to discover how individual regulator genes are connected to form complex networks that control normal blood cell differentiation, and also reveal how perturbation of these complex networks can cause leukaemia.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Discovering the structural and mechanistic principles of human helicase-loading control and its misregulation in cancer
Funder: Cancer Research UK

Abstract: We will investigate human DNA replication control. A key step during DNA replication is the loading of the replicative helicase in late M and early G1 phase of the cell cycle, which is essential for assembly of replication forks in S-phase. Helicase loading has to be exceptionally efficient, otherwise parts of the genome are left unreplicated, which results in chromosomes instability.  At the same time, helicase loading has to be completely blocked in S-phase, otherwise parts of the genome become replicated twice, which would result in hyper-recombination and chromosome breaks. For these reasons, the mechanisms that guarantee highly efficient and genome wide helicase loading have major relevance for genome stability and tumorigenesis. Currently, the underlying control principles are not well understood, in part due to the absence of a biochemical system, which is essential to fully uncover the regulatory, mechanistic and structural basis of these reactions. We have recently reconstituted human replicative helicase loading with purified proteins. Now, we will take advantage of this major breakthrough and discover how efficient helicase loading across the entire genome is achieved. We are exceptionally well placed to carry out this work, as our 10+ years’ experience with a yeast system resulted not only in the discovery of fundamental principles and structures of key complexes, but also allowed us to establish a large array of relevant research protocols. Crucially, as yeast helicase loading employs simplified regulation, the mechanisms that guarantee genome stability in healthy human cells and their misregulation in cancer cells remain largely unknown. We will use a combination of biochemical, structural, proteomic, genomic and cell biology approaches to generated a holistic insight into human helicase loading and their misregulation in the context of lung cancer. Our focus is on lung cancer, due to its poor treatment options and its susceptibility to inhibition of helicase loading. This work will be relevant to a vast array of researchers and clinicians interested in DNA replication, genome stability and tumorigenesis. Importantly, the identification of mechanisms that inhibit human helicase loading will underpin the development of novel DNA licensing inhibitors with potential for cancer therapy.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Discrimination in healthcare settings and the nocebo effect
Funder: The British Academy

Abstract: Many medication side-effects are the result of negative patient expectations rather than the pharmacological action of the drugs, thus triggering a “nocebo effect.” Negative expectations can be generated by contextual factors that contribute to the perceived quality of care. Research shows that perceived discrimination in healthcare settings among Black, Asian, and other Minority Ethnic (BAME) groups is associated with lower perceived quality of care. Yet no work has considered whether perceived discrimination contributes to experiences of nocebo effects among BAME groups, leading to potentially poorer medication adherence and health outcomes. Using a population-based sample representing the four largest UK racial/ethnic groups, this study investigates the extent to which perceived discrimination in healthcare settings contributes to nocebo effects through increased side-effect experience. Results will inform large longitudinal studies to confirm the identified causal relationships and explore BAME individuals’ healthcare experiences, and help develop interventions to reduce nocebo effects among BAME groups.


Research Activity Codes: 7.1 INDIVIDUAL CARE NEEDS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Dissecting mechanisms of alveolar repair failure and lung destruction in lymphangioleiomyomatosis
Funder: Medical Research Council

Abstract: Lymphangioleiomyomatosis (LAM) is a rare lung disease. Loss of TSC2 causes mTOR activation in LAM cells which accumulate in the lungs causing cysts by an unknown mechanism. We hypothesise that cysts form when mTOR activation causes LAM cell senescence in turn inducing senescence in surrounding alveolar type II (ATII) cells reducing alveolar repair. Using single cell sequencing we have shown that ATII cells in LAM express a senescence gene signature and in both human LAM and an animal model, senescence protein markers parallel lung damage. In the proposed work we will systematically examine how senescence leads to lung damage in LAM. We will examine alveolar epithelial cell gene transcription using single cell RNA sequencing of LAM lung cell populations from lung transplants and study early LAM biopsies by laser capture microdissection / RNA sequencing. Using gene expression and upstream regulator analysis tools we will examine cell death and repair pathways in epithelial cells and how they are regulated by LAM nodule derived proteins. Using LAM biopsies with linked clinical data we will confirm how these proteins are related to disease duration and disease activity measured by prospective loss of lung function. We will then study how senescence is regulated in vitro using novel 3D LAM nodule spheroids co-cultured with alveolar epithelial cells with individual mediators inhibited using small molecules, blocking antibodies and CRISPRcas9. We will validate these findings and test pharmacologic strategies on senescence, air space enlargement and nodule size in an immunocompetent murine TSC2 null xenograft model. Drugs affecting mTOR mediated senescence including metformin, resveratrol and mediators identified above amenable to intervention will be compared with rapalogues. These experiments will inform how lung damage occurs in LAM and other lung diseases where mTOR activation occurs, with the aim of improving treatment of LAM and potentially other lung diseases.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: RESPIRATORY
Award Title: Dissecting molecular mechanisms mediating ERK1/2 regulation of neural differentiation
Funder: Wellcome Trust

Abstract: During embryogenesis, that is the process of embryonic development after fertilisation, cells divide many times, and at some point, these cells become different from one another. This process requires turning on specific genes that make distinct cell types, such as nerve or muscle cells. My project aims to find out how this happens focusing on a specific cell type called neuromesodermal progenitors (NMP) that can contribute to two different embryonic tissues, depending on exposure to specific signals. One such signal is the Fibroblast growth factor (FGF) which regulates neural induction. It is known that inhibition of ERK1/2 activity, a protein controlled by FGF, is involved in the activation of neural genes in NMP cells. This process requires the removal of a protein complex called Polycomb, that blocks the activation of these genes. However, how the Polycomb protein complex is removed is unknown.  During my PhD project, an analysis of the proteins with changed activity upon ERK1/2 protein inactivation, will begin to dissect the molecular mechanisms regulating neural differentiation. My findings may facilitate improved protocols for directed differentiation of human cells in vitro and have wider implications for how cell state can be manipulated for therapeutic effect.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Award Title: Dissecting structural and functional contributions of promoter interactions in gene regulation
Funder: Wellcome Trust

Abstract: Understanding how complex multicellular organisms, made up from trillions of cells within multiple tissues, develop from a single fertilised egg requires turning specific genes on and off at the right place and time, in a pre-determined order. The entire process is encoded within the DNA sequence of the genome in each individual cell. In humans, there are about 20,000 genes, which encode functional units such as enzymes or haemoglobin, but these only constitute 1-2% of the DNA sequence in each cell. The DNA also contains surrounding regulatory elements that control the output of genes. There are 3 classes of such elements: promoters, enhancers and boundary elements. It is becoming increasingly clear that the roles of these elements overlap one another.   In this work, I will study the characteristics of promoter interactions and the resulting impact on gene regulation. I will be particularly interested in how promoters control gene expression by changing the three-dimensional architecture of the genome as well as the conditions by which promoters interact with enhancers. Ultimately understanding the process of gene expression will enable us to understand how these genes are normally switched on and off during development and how this goes awry in human disease.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Dissecting the crucial role of (p)ppGpp in S. aureus stress survival
Funder: Wellcome Trust

Abstract: The stringent response is a complex regulatory mechanism utilised by bacteria to survive stress. The response is controlled by the nucleotides (p)ppGpp, which function to shut down growth until conditions become more favourable. Our work has identified four ribosomal-associated GTPases (RA-GTPases) as (p)ppGpp-binding targets in Staphylococcus aureus. We showed that the activity of these RA-GTPases is inhibited upon binding to (p)ppGpp, leading to defects in ribosome assembly, slowed bacterial growth and tolerance to antimicrobials. However, our mechanistic understanding of how this occurs, the function of each RA-GTPase in ribosome maturation, as well as a general role for (p)ppGpp in stress-related processes, is limited. This project will use multidisciplinary approaches to characterise (p)ppGpp-controlled signalling pathways. Specifically, I will address three related but independent aims. I will:   1) use structure-function studies to understand how (p)ppGpp binding and inhibition of ribosome-associated GTPases impacts ribosome assembly;   2) identify additional (p)ppGpp-regulated pathways using capture-compound mass spectrometry and transposon mutagenesis;   3) determine the importance of this signalling system for virulence in immune cells.   These objectives will provide important mechanistic data on the crucial role for this signalling system in bacterial survival, and will identify essential cellular targets that may be exploited for therapeutic gain.

Lay Abstract: Staphylococcus aureus is a human pathogen responsible for a significant amount of disease worldwide. When this bacterium invades a human host it encounters a number of different stresses. The bacteria respond to this by switching on a signalling cascade controlled by two nucleotides termed (p)ppGpp, that function to shut down growth until conditions improve. Little is known about how (p)ppGpp coordinates the shutdown of diverse cellular processes. We recently discovered four GTPase enzymes involved in ribosome maturation as binding targets for (p)ppGpp. I will now investigate the function of these GTPases in the cell and ascertain how (p)ppGpp binding disrupts ribosome assembly. I will also identify additional cellular pathways that are regulated by (p)ppGpp, and uncover the role for (p)ppGpp in chronic infections. By doing so we will better understand how S. aureus can survive in the human host and can begin to design therapies to disrupt this process.

Research Activity Codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Dissecting the mechanism of action of CHD1L, a novel regulator of HIV-1 infection
Funder: Medical Research Council

Abstract: HIV remains an important cause of morbidity and mortality.  We have uncovered a novel polymorphism in African populations correlated with HIV viral load set point.  We have shown that the gene responsible is CHD1L, is a novel cellular factor negatively regulating HIV-1 infection.  To study its mechanism of action, we have knocked out CHD1L in inducible pluripotent stem cell (iPSC)-derived macrophages.  We have also created CHD1L knockdown vectors and expression vectors and are validating them in Jurkat and THP-1 cells.  We will discern cellular pathways involved in CHD1L's regulation of HIV-1 with these cells, using transcriptomic and TMT-mass spectrometry based proteomic approaches.  To identify protein binding partners of CHD1L, we will conduct SILAC-IP using lysates from uninfected and HIV infected cells. We will pinpoint the step(s) of the virus life cycle affected by CHD1L using engineered vectors expressing different fluorophores upon integration and upon activation of the viral promoter. This will be complemented by qPCR based techniques to detect the HIV genome in different stages of its life cycle, direct visualisation of the chromosomal location of viral integration sites with FISH, and assessment of nucleosome remodelling of the viral promoter with chromatin histone immunoprecipitation assays.  The results of the above studies will be followed up with specifically designed experiments.  Effects on viral integration will be confirmed with in vitro integration assays.  Protein interactions will be confirmed with traditional immunoprecipitation/western blot techniques, using relevant mutant viruses and expression vectors.  Should CHD1L alter the viral integration landscape, the distribution of the integration site will be determined.  We will also create a panel of mutant CHD1L expressors, inactivating different domains/residues of the protein to examine the specific biochemical activities of CHD1L that are crucial for its regulation of HIV.


Research Activity Codes: 5.2 CELLULAR AND GENE THERAPIES
Health Categories: INFECTION
Award Title: Dissecting thermogenesis by brown adipose tissue and skeletal muscle in lean and obese subjects
Funder: Medical Research Council

Abstract: The identification of brown adipose tissue (BAT) in adult humans ~15 years ago led to substantial interest in activating BAT to increase energy expenditure as a novel tool to treat obesity and associated metabolic disease. However, our understanding of the pathways regulating BAT activation and even how BAT utilises metabolic substrates during thermogenesis remains limited. Even the fate of glucose uptake by BAT is unclear, although we previously demonstrated high lactate production by human BAT. A major problem is the reliance on PET imaging that cannot detect uptake and release of multiple substrates in real time. While glucose uptake by BAT is reduced in obese subjects (the target patient group), whether this causes defective BAT thermogenesis or compensatory activation in other pathways is unknown. In addition, BAT positive status improves metabolic outcomes, potentially through communication with other metabolic organs but how this occurs is unclear. In this research project we will develop arterio-venous sampling of BAT and skeletal muscle as a novel technique and use this in combination with microdialysis  to to quantify substrate utilisation by BAT, skeletal muscle and white adipose tissue (WAT) in lean and obese volunteers during warm and cold exposure in real time. We will also infuse 13C-glucose to determine the fate of glucose in vivo and the fate of multiple substrates in vitro using our primary human brown and white adipocyte and myoblast cell models. We will determine the role of the lactate receptor in BAT using our in vitro models and also in vivo using mice with global disruption of this receptor. Finally, we will perform proteomics/peptidomics analyses on blood and dialysate to identify the in vivo BAT secretome for the first time to identify potential candidates with therapeutic potential. This research will identify key thermogenic pathways and any dysregulation in obesity, this may identify targets for subsequent therapeutic manipulation.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: METABOLIC AND ENDOCRINE
Award Title: Do non-steroidal anti-inflammatory drugs (NSAIDs) reduce the appearance of sacroiliac joint bone marrow oedema on MRI, in spondyloarthritis?
Funder: Versus Arthritis

Abstract: Active inflammation in the sacroiliac joints, observed on magnetic resonance imaging (MRI), is used increasingly in the diagnosis of axial spondyloarthritis.  Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the management of patients with spondyloarthritis.  However, it is not known whether the MRI appearance of active inflammation in the sacroiliac joints is affected by NSAID use.  We hypothesise that a significant proportion of patients with axial spondyloarthritis who, in the absence of NSAIDs exhibit evidence of bone marrow oedema consistent with active sacroiliitis would, in the presence of such medication, exhibit no such evidence of active sacroiliitis.

We propose a non-randomised cross-over trial.  Male HLA-B27+ patients with axial spondyloarthritis, recruited from rheumatology clinics, will be asked to undergo a one-week NSAID-free wash-out period, after which they will receive an MRI scan (baseline) of their sacroiliac joints.  Participants will then re-start NSAID therapy, as per their usual care.  Six weeks after re-starting therapy, those with a positive scan for sacroiliitis will receive another MRI scan (follow-up).

We will determine the proportion of participants with MRI-observable sacroiliitis that resolves with NSAID use.  The results of the proposed study will inform recommendations regarding medication use prior to MR imaging in spondyloarthritis.


Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM