NIHRDataInsights/HRCSData huggingface dataset:
Title: Pathobiology of alpha-1-antitrypsin deficency and the serpinopathies
Funder: Medical Research Council

Abstract: We have used a wide range of techniques to show that naturally occurring mutations in members of the serine proteinase inhibitor (serpin) superfamily result in abberant conformational transitions to cause disease. The most common of these is the sequential linkage between the reactive centre loop of one molecule and beta-sheet A of another. This process of loop-sheet polymerisation results in the retention of ordered serpin polymers within the cell of synthesis. Polymerisation of mutants of antitrypsin, antithrombin, C1 inhibitor and antichymotrypsin cause cirrhosis, thrombosis, angioedema and emphysema respectively. Perhaps most striking is our description of the same process in a neurone specific serpin, neuroserpin, to cause a novel dementia that we have called Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). A central feature of these conditions is a genotype-phenotype correlation that can be explained by the rate of intracellular polymerisation. In view of their common mechanism we have grouped these diseases of the serpins together as the serpinopathies and have used them as a paradigm for a broader class of disorders that we have called the conformational diseases. The serpinopathies provide a structurally defined model of protein aggregation in association with disease. We propose to use the small molecules, crystal structures, cell lines, monoclonal antibodies, fly models and the genetic screen that were generated in the last programme grant to address the following specific questions: (i) what are the conformational transitions underlying the serpinopathies? (ii) what is the effect of small molecules that block the polymerisation of alpha-1-antitrypsin? (iii) what is the cellular response to the retention of ordered serpin polymers within the endoplasmic reticulum? (iv) can we prepare monoclonal antibodies to latent alpha-1-antitrypsin and neuroserpin in order to define their role in disease? (v) what is the role of polymers in lung disease in alpha-1-antitrypsin deficiency? These studies, although focused on alpha-1-antitrypsin and neuroserpin, are applicable to many of the mutations in serpins that underlie the serpinopathies. The long-term aim of our work is to understand mechanisms of disease caused by the serpinopathies (from pathological conformational transitions to pathways of cell toxicity) so that we can develop novel therapeutic strategies to treat the associated clinical syndromes.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Investigating how structural factors affect vulnerability to violence and risk reduction among sex workers in Peru
Funder: Medical Research Council

Abstract: Sex workers face multiple physical and mental health risks, including violence, HIV, coercion, drug use, stress and depression. Despite widespread abuse, sex workers have received little attention in global reviews of violence. Violence can have severe physical and emotional health consequences and increases vulnerability to HIV. Stigma may further exacerbate vulnerability to physical and psychological violence, and affect emotional health and capacity to manage risk. The World Health Organization advocates violence reduction interventions among sex workers. Structural approaches - which address social, environmental and political factors - are considered crucial for HIV prevention. The concept of ‘structural violence‘ provides a framework to study the consequences of different forms of violence, physical, emotional and ‘symbolic‘ (such as stigma). Peru has among the highest rates of domestic violence globally and a high prevalence of abuse against female sex workers, providing an excellent case study to investigate how structural factors bring about and sustain physical, emotional and symbolic violence, and affect capacity to manage risk - an under-researched area. Aim: To investigate how structural factors affect vulnerability to violence and mediate capacity for risk reduction among male, female and transgender sex workers in Peru. Objectives: (1) To examine associations between structural factors, physical, emotional and symbolic violence among sex workers (2) To explore pathways through which structural, physical, emotional and symbolic violence mediate capacity to manage emotional health and other risks among sex workers (3) To analyse how key agencies mediate structural factors which affect the risk of violence among sex workers Methods: A mixed methods study, set in Peru, comprising: A) A systematic literature review of the risk of violence among sex workers globally, followed by a secondary analysis of data from the ‘Sex Worker Empowerment Survey‘ in Peru, examining associations between structural factors, violence and other health outcomes; B) a qualitative study of structural factors affecting risk of violence, how different forms of violence interact, and how these affect capacity to manage health risks, using in-depth interviews with sex workers; and C) a stakeholder analysis to explore key agencies‘ perspectives on structural determinants of violence among sex workers, and their potential role in mediating these factors, using semi-structured interviews. Outputs: Findings will inform structural interventions to reduce violence and other health risks among sex workers globally, as well as feeding directly into national policy in Peru. This study will also identify scope for further research addressing the structural context of risk.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: The assessment of pain using facial expressions in laboratory mice, rats, rabbits and macaques
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Facial expressions are routinely used to assess emotions such as pain in humans, especially in the non-verbal (e.g. cognitively impaired and neonates). Recently, the work of Langford et al. (2010) has demonstrated that mice exhibit facial expressions in response to a range of routine nociceptive tests. If these facial expressions are a direct response to pain, then this may offer a new method of assessing pain in animals. The assessment of pain using facial expressions may overcome some of the limitations associated with current best practice of using behaviour. The administration of opioid analgesia itself does not appear to induce changes in facial expressions, confounding the assessment of pain. Facial expressions may be more directly related to the emotional rather than sensory component of pain, and it is the emotional component that is the most critical. In assessing facial expressions we could take advantage of our natural tendency to look at face, which could increase the effectiveness of this method. The assessment of pain using facial expressions should be less time consuming to undertake, allowing effective indicators to be identified for more procedures and species. Our aim is to investigate whether facial expressions can be objectively and reliably used to measure post-procedure pain in a range of laboratory animal species either alone, or in conjunction with other techniques. Initially we will assess whether facial expressions in mice change following procedures associated with both acute (e.g. post-surgical) and chronic (e.g. neoplasia) pain. Once we have successfully validated the use of facial expressions for assessing post-surgical pain in mice we will assess whether a similar approach can be used to assess post-surgical pain in other species, including rats, rabbits and macaques. It is important to note that we currently have no objective method of assessing post-operative pain in non-human primates. We will demonstrate that facial expressions can: (1) Assess post-procedural pain as well as responses to nociceptive testing in mice; (2) Overcome the limitations associated with behavioural pain assessment; (3) Rapidly and objectively score pain in a variety of species; (4) Potentially be a more sensitive measure of pain; (5) Determine the duration and severity of post-procedural pain by correlating them with behavioural indicators of pain in a range of species; (6) Potentially assess the affective component of pain in animals; (7) Evaluate the efficacy of methods to alleviate pain (e.g. analgesic administration), and to develop and apply more humane endpoints.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Over three years to study mitochondrial quality control mechanisms as therapeutic targets in genetic mitochondrial disease.
Funder: Action Medical Research

Abstract: Background_x000D_ Mitochondria are tiny structures within cells that provide the energy needed for most of a cell's activities. Remarkably, mitochondria contain their own DNA that codes for some of the key proteins required for normal mitochondrial function. Individual cells may contain hundreds if not thousands of copies of this mitochondrial DNA. In some genetic mitochondrial diseases, a gene mutation within the mitochondria means that they cannot produce enough energy and therefore affected cells don't work properly and may die. This results in a range of devastating diseases mainly affecting the brain and muscles, causing severe disability and reduced life expectancy. Over time, children with mitochondrial disease typically develop muscle weakness, and Central Nervous System abnormalities that may include progressive loss of sight and hearing and dementia. Mitochondrial diseases are estimated to affect one in 5,000 babies born in the UK. There is no cure for these conditions and treatment options are very limited. _x000D_The severity of disease can vary widely, even between children who have the same gene mutation. One explanation for this is that they have different proportions of normal and affected mitochondria in their cells. The body naturally removes abnormal mitochondria by a process known as autophagy and repairs or replaces them by another process known as biogenesis. Together, these two processes act as a type of ongoing quality control and determine the overall 'health' of mitochondria within cells. _x000D_The research project_x000D_ The researchers propose that any treatment which increases the ratio of normal:abnormal mitochondria should improve overall mitochondrial function and slow or prevent the development of symptoms of mitochondrial disease. In the laboratory, the team will test whether certain drugs or nutrients can be used to increase mitochondrial biogenesis and/or stimulate autophagy to determine whether this results in a reduction in the proportion of abnormal mitochondria and an overall increase in mitochondrial health. Several of the drugs being tested are already licensed for use in patients with other disorders, so if this study shows that they are effective in mitochondrial disease, the researchers hope they could quickly be progressed into clinical trials to help establish new treatments for children with these devastating conditions.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Fit for Work Evaluation
Funder: Department for Work and Pensions

Abstract: Fit for Work service is a significant initiative for DWP. This research seeks to understand whether it is reaching those most in need

Lay abstract: Fit for Work service is a significant initiative for DWP. This research seeks to understand whether it is reaching those most in need

Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Work and Health Programme Evaluation
Funder: Department for Work and Pensions

Abstract: Evaluation of the national Work and Health Programme - a contracted provision to help individuals with health and disability needs into work

Lay abstract: Evaluation of the national Work and Health Programme - a contracted provision to help individuals with health and disability needs into work

Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Barriers to self-employment for people with disabilities or health conditions
Funder: Department for Work and Pensions

Abstract: Qualitative and quantitative research with individuals with disabilities or health conditions, to understand the barriers they face in becoming and maintaining self-employment

Lay abstract: Qualitative and quantitative research with individuals with disabilities or health conditions, to understand the barriers they face in becoming and maintaining self-employment

Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Network for research on death, dying and end of life care among Syrian refugees in Lebanon
Funder: Economic and Social Research Council

Abstract: The Syrian Civil War has created one of the worst humanitarian crises in history. Around 5 million Syrians have fled their country to escape the prolonged horror and violence of the conflict and more than one million of them are in Lebanon. Over 4000 refugees cross into Lebanon on a daily basis, overwhelming its already fragile social, political, and economic infrastructure. On reaching Lebanon, new troubles confront the Syrian refugees who must now endure the suffering and hardships of the temporary camps. This refugee movement has put a huge strain on the resources and capacity of the Lebanese government and local communities. The Lebanese health system has seen a massive influx of additional demand and is struggling to cope. One particular aspect of the problem is the suffering of older refugees. Often at the bottom of the pecking order, the needs of older refugees are frequently neglected, unrecognised or ignored. Yet about a half of these older people are known to have chronic health problems and are at risk of dying through lack of access to healthcare. Others have advanced disease and require palliative treatments to manage pain and other symptoms. Very little is known about how these treatment and end of life care needs are being addressed. Although some palliative care services exist in Lebanon they have limited resources and lack the capacity to deal with the level of need in the refugee camps. Yet palliative care availability and access have been acknowledged as fundamental human rights. The main purposes of the project are therefore: 1) to strengthen research capacity to investigate end of life care issues and needs among refugees 2) to enhance related cooperation and coordination between researchers in Lebanon and the UK in order to build capacity for high quality new studies and interventions that can address these problems. To foster such a network, the project will bring together a mixture of expertise in special workshops focussed on end of life care for refugees in Lebanon. It will conduct a rapid appraisal of the issues and look at ways to develop research responses. It will provide mentoring and training to local researchers from international experts in order to build expertise and capacity. It will also lead to a short film on the issue to raise awareness and sensitize others to the issue. By these means the network will contribute to the development of research, policies and plans to promote end of life care for Syrian refugees in Lebanon. The lessons learned will in turn be relevant to other similar humanitarian emergencies elsewhere.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Looked-after children in Wales: An analysis of the backgrounds of children entering public care
Funder: Economic and Social Research Council

Abstract: The doctoral research around which my fellowship is centred explored the differences between local authorities in Wales in the rates at which they place children in out of home care, referred to as being a 'looked after'. The research is based on a detailed quantitative analysis of approx. 15,000 children who were 'looked after' in Wales in a six year period from 2008 to 2014. The research identified differences in social work practice between local authorities and also highlighted the relationship between neighbourhood deprivation and rates of children in care. Whilst there have been similar studies undertaken in England, there have been no such studies undertaken in Wales and this has generated a great deal of interest in the study from those involved in both child welfare policy and practice. One of the aims of the fellowship is therefore to disseminate the study's findings to social workers, managers, policy makers and elected members with responsibility for child welfare across Wales and to engage them in discussions on the implications of them for policy and practice. Dissemination of the findings will be through a range of routes including summary reports, blog posts, seminars and articles for sector specific publications. The intention is also to share the findings with an academic audience, including those involved in educating student social workers, through the production of a number of peer-reviewed journal papers. There is a lack of quantitative research and research skills within social work research in the UK. This situation reflects that found more widely in the social sciences, but arguably it is especially acute in social work. The second aim of my fellowship is therefore to build on the quantitative research skills I have gained through the doctorate, both in order to develop my own skills for future research and to contribute towards building capacity further in social work research. During the fellowship I will undertake a number of intensive quantitative methods courses. I will also visit a world reknowned research centre that undertakes research on children in out of home care using the quantitative analysis of large scale longitudinal administrative data. The third aim of the fellowship is to develop my research network with the intention of identifying potential collaborators with which to develop research ideas and funding proposals for future research.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Contexts of Violence in Adolescence Cohort Study (CoVAC)
Funder: Economic and Social Research Council

Abstract: Intimate partner violence, and violence during childhood are extremely common exposures, and cross-sectional data indicates they are associated. However data from cohort studies is equivocal and little is understood about mechanisms, especially in low income country settings. We propose an efficient new cohort study that uses data from the existing Good Schools Study in Uganda as a baseline. The main aims of our cohort study are to: 1) examine the epidemiology and patterns of violence exposure in early adolescence; 2) understand which patterns of early adolescent exposure to violence are associated with violence use and experience in later adolescence and young adulthood; 3) explore the pathways by which violence in early adolescence, later adolescence and young adulthood are associated and how context encourages or interrupts these associations. We will conduct a mixed methods study. We have already collected quantitative survey data from 3438 adolescents in 2014 when they were about age 11-14, as well as their teachers and a subsample of their caregivers. We will do a second survey in 2018 (age 15-18 years) and a third survey in 2021 (age 18-21 years). Analysis will involve fitting mixed regression models and structural equation modelling. Qualitative data will be collected from 36 adolescent participants who will be followed up at four time points from 2018 to 2021, with data also collected from peers, families, school staff and community members. Drawing on ethnography and participatory research, our analysis will focus on how social processes shape individual biographies over time, following varying experiences of violence, and identifying the contextual dynamics that perpetuate or prevent violence. This research will generate novel findings which inform the development of violence prevention interventions internationally. Our research team will use the results directly to develop additional programming in Uganda.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: DISPUTED AETIOLOGY AND OTHER
Title: Genetic basis of limb and gut development and dysmorphogenesis
Funder: Medical Research Council

Abstract: Mouse model systems provide insights into the process of organ development. The goals of these studies are to examine mouse mutants that model congenital abnormalities in order to understand both the normal processes that are responsible for organogenesis and the abnormalities that disrupt development and lead to disease. Focusing on the genetics of the mouse, we examine two aspects of development. Firstly, we explore the mechanisms essential for normal skeletal development. In particular, we investigate limb patterning mechanisms required to generating the array of skeletal elements that constitute the mammalian limb. Expression of the Shh gene is central to the mechanism that patterns the limb. Correct spatio-specific Shh expression is required for normal patterning of the digits. We investigate the mechanisms for the long-range spatiotemporal regulation of Shh and the mechanism by which point mutations residing in the regulator manifests PPD (preaxial polydactyly). We propose to identify sequence elements which may interact with the ZRS and attempt to establish factors required for regulating expression through the ZRS. In addition we propose to use the ZRS as a tool to explore the molecular mechanisms required for patterning the mammalian limb. Secondly, we investigate the development of the gut; in particular, mechanisms that define the left-right asymmetry of organ systems. One aspect is to focus on the spleno-pancreatic region. These studies give insights into mesodermal/ endodermal interactions important for directing early gut development. We have hypothesized that the splanchnic mesoderm-derived SMP, by coordinating mesenchymal functions, plays a role in the morphogenesis of the gut region which includes the stomach, duodenum, pylorus, and pancreas. The Bapx1 gene resides near or at the top of a hierarchy of genes that controls morphogenesis in this region. The mesenchyme in which these genes are expressed is crucial in sending morphogenetic signals to the endoderm. The mesenchyme specifically grows to the left under the control of the SMP which itself is controlled by the L/R signalling cascade. We plan to investigate the mesenchymal signals regulated by BAPX1 that signal to the endoderm to define the stomach/duodenal boundary, and regulate the rate of cell division. We also plan to investigate the Bapx1 role that is crucial later in development to define an important boundary between the spleen and pancreas. In the absence of this boundary differentiated pancreatic acini are induced to transform to ectopic gut-like structures. Finally, we have made a mouse model for the Matthew Woods syndrome (or PDAC syndrome) which effects heart asymmetry, lung and visceral development and patients that survive are mentally retarded. The mutation affects retinoic acid signalling and we are investigating the role of the gene on development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: DISPUTED AETIOLOGY AND OTHER