NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Measuring and enhancing resilience to chronic pain in elderly patients with arthritis using neurofeedback
Funder: Dunhill Medical Trust

Abstract: This research proposes to test and develop an alternate therapeutic strategy for elderly patients with chronic
arthritic pain, whose pain is not adequately controlled by analgesics or who prefer not to take analgesics.
We have shown that the expectation of pain relief is associated with increased alpha waves in the frontal
cortex. These alpha waves are thought to mediate top-down control in the brain. Initial studies from our
group have demonstrated substantial changes in the power of alpha waves in the frontal cortex in healthy
volunteers subjected to moderately severe shoulder pain over several minutes. We think that this may be a
neural signature of pain resilience.
We would like to develop these studies further to confirm our initial findings, establish a signature for pain
resilience and to use this to develop robust methods of neurofeedback that will provide useful and safe therapy
for elderly patients with chronic arthritic pain.

Lay Abstract: Chronic pain in older people with arthritis is a major cause of disability and consulting in primary care.
Available therapies are limited, including pain killers which may cause side-effects.
We have identified potential brain mechanisms for vulnerability and resilience to chronic pain. The brain in
patients with chronic pain is always expecting bad things to happen and tends to focus on the negative aspects
of pain experience. These effects can be reversed by cognitive (talking) therapy. This increases control by
forebrain structures of other areas of the brain responsible for pain perception. We think we can measure brain
waves relating to increased control of pain. This project will identify a detailed brain signature of resilience to
pain using recordings from the brain surface. We will use this signature to train elderly patients to increase their
resilience to pain by giving them immediate feedback on how their brains are responding.

Research Activity Codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health Categories: MUSCULOSKELETAL;NEUROLOGICAL
Award Title: Mechanism of HSV-1 pUL51/pUL7 focal adhesion stabilization
Funder: Wellcome Trust

Abstract: Herpesviruses cause a significant degree of global morbidity but also provide powerful tools with which to probe intricate cellular processes. Herpes simplex virus pUL51 and pUL7 are conserved across herpesviruses and form a complex in infected cells. This complex promotes wrapping of nascent virions and recent work in our lab has shown it also localises to and stabilizes focal adhesions, reducing the ability of infected cells to detach from the substrate and potentially enhancing cell-to-cell spread. We will use live-cell fluorescence microscopy to investigate how the pUL51/pUL7 complex modifies focal adhesion dynamics during infection. Additionally, we will use quantitative mass spectrometry to identify binding partners of the pUL51/pUL7 complex at focal adhesions. The interactions of the complex with these cellular partners will be structurally and biophysically characterised, allowing us to design specific mutations that disrupt focal adhesion association but maintain envelopment functionality. We can then specifically probe the effect of focal adhesion modulation upon replication and cell-cell spread of the virus. Understanding how herpesviruses modify focal adhesions to enhance spread may open up new avenues for therapeutic and vaccine development as well as providing insights into focal adhesion biology.


Research Activity Codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION
Award Title: Mechanism of Tar-Induced Pyroptosis of Human Coronary Endothelial Cell in Myocardial Infarction Caused by Plaque Erosion
Funder: The Academy of Medical Sciences

Abstract: Acute myocardial infarction (AMI) is one of the major diseases which endanger human health. The main causes of AMI currently include three pathological mechanisms: plaque rupture(PR) , plaque erosion(PE) and calcified nodules. For a long time, we have been working on the prevention and treatment of PR, ignoring that about one-third of AMI is caused by plaque erosion. Furthermore, due to the unclear understanding of the mechanism of PE and the lack of effective in-vivo diagnostic methods, the treatment of PE has become an international problem that needs to be solved urgently. Our previous study found that the occurrence of PE is closely related to smoking, but absent of other cardiovascular risks, such as diabetes mellitus, hypertension and hyperlipemia.. Therefore, our project is to study the relationship between smoking and PE. The results of the study will provide an important theoretical basis for the precision management of AMI and a potential new target for intervention.

Lay Abstract: Plaque erosion (PE) is one of most important pathological mechanisms of acute myocardial infarction (AMI). Our group reported for the first time in the world that optical coherence tomography (OCT) could identify PE in vivo and developed a new algorithm for characterising PE by OCT. Importantly, we found that the occurrence of PE is closely related to smoking. Autopsy study showed that extensive endothelial cells death and detachment was observed at the site of plaque erosion, resulting in thrombosis ultimately. But the exact mechanism led to endothelial cells death is not clear. Our in vitro study showed that tar, the main component of tobacco, can induce a special type of death in endothelial cells, called pyroptosis, by activating NLRP3 inflammatory body. Therefore, we speculate that tar-induced endothelial cell pyroptosis may play a central role in thrombosis caused by PE. The present project, as an extension of our previous study, will focus on mechanism of endothelial cells death and thrombosis in PE. Our goal is to elucidate the molecular mechanism of tar-activated NLRP3 inflammatory bodies inducing endothelial pyroptosis. In addition, we will innovatively apply autopsy to confirm the important role of endothelial pyroptosis in PE .The results of the study will provide an important theoretical basis for the precision management of AMI and a potential new target for intervention.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CARDIOVASCULAR
Award Title: Mechanisms and regulation of PEPITEM secretion
Funder: Wellcome Trust

Abstract: The migration of immune cells such as T-lymphocytes to areas of inflammation plays an important role in the inflammatory response. T-lymphocyte migration follows a circadian (daily) rhythm, with more T-lymphocytes migrating into tissues in the morning than the evening. If this process is not carefully regulated, this can lead to an exaggerated inflammatory response which contributes to diseases. PEPITEM is a small peptide hormone which inhibits T-lymphocyte migration and is made by another type of immune cells, B-lymphocytes. Patients with inflammatory diseases cannot make PEPITEM in sufficient quantities to control T-lymphocyte migration. Our preliminary studies indicate that a protein able to cleave other proteins (protease) is responsible for PEPITEM release from B-lymphocytes and that this might be under circadian control. In my project, I aim to identify the protease that leads to PEPITEM release, and investigate how the PEPITEM pathway follows circadian oscillations. I will look at the expression of genes and proteins involved in the PEPITEM pathway at different time of the day to see how this pathway is regulated by circadian rhythms. This project will help to understand the dysregulation of inflammation that occurs in many chronic inflammatory diseases.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE;INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Mechanisms in Disorders of Energy Balance
Funder: Medical Research Council

Abstract: Obesity and its metabolic consequences are major threats to public health with an unmet need for improved therapy and prevention. Understanding the mechanisms involved in the control of human energy balance is essential to develop new treatments. By focusing upon a cohort of patients with severe early onset obesity, we have previously uncovered novel, highly penetrant alleles causing childhood obesity and gone on to establish the mechanisms of molecular dysfunction in many of these conditions.  Over this quinquennium our work on the biology of energy balance and its disorders will have three broad aims: i) To continue to explore how human genetic variation that strongly predisposes to disorders of energy balance such as obesity exerts its effects at the molecular, cellular, organismal and human level and, where possible, to translate that knowledge into improved diagnosis or treatment ii) To further understand how disruption of particular imprinted genes can lead to obesity phenotypes. This will include further exploration of the bi-stable, potentially stochastic pattern of obesity seen with loss of Nnat and the development of a murine model of PWS that exhibits hyperphagia and obesity iii) To explore aspects of the basic biology underlying variation in leptin production and secretion, and to establish the extent to which a potentially clinically relevant phenotype of partial leptin deficiency might exist within the broader population of people with obesity


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: METABOLIC AND ENDOCRINE
Award Title: Mechanisms of Fibre Toxicity (cross-Unit project)
Funder: Medical Research Council

Abstract: It is well established that exposure to naturally occurring mineral fibres, such as asbestos, is associated with development of disease, including incurable mesotheliomas. However, the potential of newer manufactured nanofibres e.g. carbon nanotubes (CNTs) to trigger similar disease-associated molecular changes is under-explored. Extensive studies on the toxicity associated with exposure to fibres has led to the fibre pathogenicity paradigm (FPP); the degree of toxicity is related to the diameter, length and biopersistence of the fibre. The data suggest that nanoparticles with a high aspect-ratio (HAR) - long thin rigid fibres - are potentially toxic. By exploiting the combined expertise of two laboratories, the aims of this cross-Unit programme are built around the hypothesis that exposure to biopersistent nanofibres with a HAR initiates a series of events that leads to the development of mesothelioma. Detailed mechanistic information is therefore essential to:  1)  construct a “nanofibre-toxicity pathway”  2) identify the key molecular changes that drive the very prolonged process (~40 years) of tumour development. 3) identify novel biomarkers of exposure prior to disease progression. By employing longitudinal studies in animal models, and comparing this with changes in patients with mesothelioma, we will able to identify at which point these alterations occurred during disease development and thus establish their position in the toxicity pathway. Through the exposure of animals to distinct types of fibres (long CNTs and different classes of engineered nanomaterials, using long asbestos fibres as a reference), we aim to determine the differences and commonalities between these agents at a molecular level and use this information to understand the potential hazards associated with human exposure to CNTs. This research is essential since there is a lack of information about the consequences of pleural exposure of mammals to long CNTs, and the mechanisms underlying carcinogenesis induced by these materials, have not been elucidated.   The data generated through these integrated projects will increase our understanding of the processes of disease development associated with pathogenic fibre-induced toxicity, provide new biomarkers to assess the exposure of the population to potential hazards and inform the future ‘safe by design’ of these new classes of nanomaterials.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Award Title: Mechanisms of lineage restriction in development and reprogramming.
Funder: Wellcome Trust

Abstract: Mechanisms that lead to the establishment and maintenance of cell identity are paramount for organismal health. They also underpin successful cellular reprogramming for disease modelling and cell replacement therapies. We will investigate the roles played by the epigenome and co-factors in regulating lineage transcription factor-mediated establishment and stabilisation of cell fate in vivo and in vitro.
 
 
 
Firstly, controlled activation and degradation of engineered transcription factors (TFs) will be used to challenge cell identity in developing frog embryos. We will compare transcriptional profiles and chromatin landscape in “permissive” tissues that respond to TF over-expression by undergoing full lineage reprogramming, and “non-permissive” tissues that resist reprogramming, as well as probing heterogeneity of transcriptional response in individual cells. Secondly, mechanisms responsible for differential response to TF will be identified through interference with the epigenome as well as via alteration of the co-factors repertoire present in embryonic tissue. Finally, we will explore mechanisms underlying lineage fidelity in mammalian ES cells that have been engineered to co-express TFs specifying conflicting lineages.
 
 
 
Overall, this work will reveal how the response to lineage determining TFs is controlled by integration of epigenetic features and co-factor availability in both the developing embryo and in reprogrammed mammalian cells.

Lay Abstract: Cells in the developing embryo need to know how to become one cell type or another and how to keep that identity throughout life, something that is controlled by the activity of specific parts of the DNA and stabilised by the binding of control proteins. In our project, we will investigate why some cells in the developing frog tadpole are more resistant to changing their identity that others when we experimentally manipulate the proteins that direct cell fate.  We will also see what happens when we try and make one cell adopt two identities at the same time.  Increased understanding of the changes in DNA and proteins that cause adoption of stable cellular identity will help us explain how normal development is regulated.  It will also aid us in making new cells to repair and replace those damaged in many sorts of diseases such as diabetes and Parkinson’s disease.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: NEUROLOGICAL;GENERIC HEALTH RELEVANCE
Award Title: Mechanisms underlying neuronal-microglia interactions during development in health and disease
Funder: Medical Research Council

Abstract: The formation of the brain involves diverse populations of cell types undergoing a precise sequence of developmental processes, that vary in space and time. However, to create functional circuits, these diverse cell types need to come together at appropriate times and numbers for cortical wiring to begin. This involves some coordination between cell types to ensure appropriate types and numbers are present at the right time and place. The lack of or dysregulation of this coordination during development can lead to cellular imbalance that ultimately impacts normal cortical circuit function and leads to dysfunctions as seen in neurodevelopmental disorders. Here, I propose to understand how this coordination occurs between two different cell lineages, namely pyramidal cells and microglia, during development. Specifically, I will study the molecular mechanisms as to how microglia sense and react to changes in pyramidal cells and tune their development accordingly. By using different types of transgenic mice and genetic manipulations, I aim to determine how pyramidal cells can affect the development, maturation, survival and function of microglia, by addressing the following goals: (1) Characterise the development of microglia in the developing mouse neocortex and establish the impact of alteration of pyramidal cell activity on microglia development. (2) Elucidate the molecular mechanisms involved in the establishment of neuronal-microglia proportions, by analysing the differentially expressed genes to identify specific ligand and receptor pairs. (3) Determine the impact of genetic mutations that has been linked to neurodevelopmental disorders, specifically in pyramidal cells, on microglia development and function, by analysing microglial cell biological behaviour, transcriptional changes and impact on rodent cognitive and behaviour tasks.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL;MENTAL HEALTH
Award Title: Mechanistic investigation of the cross-talk between spliceosomal complexes and polyadenylation factors
Funder: Wellcome Trust

Abstract: Splicing and polyadenylation are two essential steps of gene expression that account, to a great extent, for the complexity of eukaryotes. The two processes are catalysed by the spliceosome and the polyadenylation apparatus – two macromolecular machines of megadalton-size which contain more than 70 and 20 proteins, respectively.
 
The two machines associate physically to form composite assemblies, where cross-talk events support emerging layers of regulation of splicing and polyadenylation. These assemblies are primarily unexplored from a mechanistic perspective, due to their excessive size, complexity and dynamics.
 
By employing state of the art technologies and our long-standing expertise in the structural biology of splicing, the time is now ripe for a thoroughgoing investigation of these assemblies. Thus, we aim to stall and isolate composite assemblies relevant for: (i) the coupling between splicing and polyadenylation, (ii) the definition of exons during constitutive and alternative splicing and (iii) protection of genes from premature polyadenylation. Afterwards, we will characterise their 3D structures and functions by electron cryo-microscopy and complementary biochemical methods. The proposed research is expected to be eye-opening and bring a substantive contribution to our understanding of how fundamental processes of gene expression integrate mechanistically.

Lay Abstract: Building an organism requires accurate reading and processing of instructions encoded in the DNA. This task is accomplished by nano-molecular machines able to process the encoded information in a combinatorial fashion, producing a high complexity of the organisms out of a limited set of instructions. Inaccurate processing can cause various diseases.
 
Two information-processing nano-machines bind one another to act in a coordinated manner, as composite assemblies. The working of these supra-molecular entities is unclear, as we don’t know how all of their working parts look like and how they are organized in space and coordinated in time.
 
Our goal is to characterize the 3D structure of the composite nano-machines in different snapshots. The vivid picture that would result should enable our understanding of how the information stored initially in DNA is processed at a superior level.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Medical Pluralism at the Periphery: Health, Modernity and Ethnicity in Guangxi, China, 1920s-1950s
Funder: Wellcome Trust

Abstract: In many ethnic-minority regions of China, multiple forms of medical practice and knowledge play a role in healthcare. As most of the major hospitals mainly serve cities, many people in rural areas can only access the health services provided by village practitioners who have studied one-year courses in medical institutions. Some people in ethnic minority communities also turn to religious forms of treatment, such as enchantment and rituals, which have often been the traditional means of healthcare. This means that multiple forms of healthcare coexist, but there is a lack of extensive, historically-grounded research on what this means in practice. My project will explore how this situation can be traced back to the early and mid-twentieth century by studying medical plurality in Guangxi, a peripheral, multi-ethnic province in Southwestern China. I will consider how medical practices and knowledge in different communities – Western missionaries, Western-trained doctors, Han Chinese and ethnic minorities – interacted with each other. A historical analysis of these relationships will allow us to understand the tensions that exist between different forms of healthcare today, and suggest pathways toward more cooperative forms of engagement among different medical communities.

Lay Abstract: In many ethnic-minority regions of China, multiple communities of medical practice and knowledge coexist uneasily. As most hospitals mainly serve cities, many people in rural areas can only access the health services provided by village practitioners who have studied a one-year course in medical institutions. Some in ethnic minority communities also turn to religious forms of treatment, such as enchantment and rituals, which have often been the traditional means of healthcare. My project will provide a historical analysis of how different communities of medical practice and knowledge interacted with each other in Guangxi, a multi-ethnic, peripheral province in Southwestern China, throughout the first half of the twentieth century. A historical analysis of these relationships will allow us to understand the tensions that exist between different forms of healthcare today, and suggest pathways toward more cooperative forms of engagement among different medical communities.

Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: GENERIC HEALTH RELEVANCE