NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Gene Editing in X-Linked Agammaglobulinaemia
Funder: Medical Research Council

Abstract: X-linked agammaglobulinemia (XLA) is caused by a mutation in Bruton's Tyrosine Kinase (Btk) which is encoded at the Xq22.1 locus. When developing lymphocytes reach the pre B-Cell phase they express  a pre B Cell receptor and after cell surface expression it dimerises sending survival signals via Btk. Mutations of this molecule lead to the cessation of B-cell development. Patients therefore have absent B Cells and no detectable Immunoglobulins.    This project will assess the CRISPR-Cas system of gene editing to correct this mutation.  This involves nucleofection of cells with the Cas 9 protein complexed with a guide RNA complementary to our chosen target. This leads to a double stranded DNA break (DSB) at the Btk gene locus. Subsequently a Adeno Associated Virus 6 vector will be used to introduce a normal Btk minigene gene into the locus. Following optimisation of the technique in a Btk knockout DG75 cell line, we will trial it in CD34+ cell from healthy donors and then XLA patients. CD34+ cells will be separated from blood using Magnetic-Activated Cell Sorting. Editing efficiency will be determined by Digital Droplet PCR. Subsequently, we will perform in vitro comparisons will assess the function of gene edited patient cells. To assess for off target effects we will use GUIDE-sec (Genome-wide, unbiased identification of DSBs enabled by sequencing). This method involves tagging any DSBs in the genome with a blunt double-stranded oligodeoxynucleotide (dsODN). Integration points are then identified using PCR amplification and sequencing of products.   We finally aim to test gene edited cells in a NSG mice model. Primary and secondary transplantation will be performed and each experiment will consist of 3 groups (negative control, gene edited group and positive control). To assess restoration of the humoral immune system we will perform flow cytometry to determine B Cell numbers, test vaccination, Immunoglobulin quantification and cell proliferation assays.


Research Activity Codes: 5.2 CELLULAR AND GENE THERAPIES
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Gene therapy for Non-Ketotic Hyperglycinemia
Funder: LifeArc

Abstract: Non-Ketotic Hyperglycinemia (NKH) is a life-limiting inherited metabolic disease that affects the chemical changes in cells of the brain and liver. It is marked by a build-up of glycine (an amino acid) in the body because of a mutation in genes that encode parts of the glycine cleavage system (GCS).

Most patients carry mutations in glycine decarboxylase, an enzyme that is part of the GCS. NKH becomes apparent in babies soon after birth with lethargy, breathing difficulties and neurological problems, including epilepsy and developmental delay. Current treatments for NKH have limited effect and there is no cure.

The project aims to develop gene therapy for NKH using a virus-based vector, to restore the activity of GLDC in the brain. This strategy has the potential to treat any patient with a loss-of-function mutation in GLDC and could be used for the other main NKH-causing gene, AMT.

In this project, the team will test novel gene therapy vectors in a GLDC-deficient mouse model that displays key features of NKH. It will evaluate whether treatment restores GCS activity and whether this can reduce metabolic defects in the brain, normalise gene expression and improve neurological features. As a step towards clinical implementation, the team will also test whether the impact lasts over time and is safe. This will support development towards the final stages of pre-clinical testing – including the start of GMP manufacture and pre-clinical studies to support application for a clinical trial.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health Categories: METABOLIC AND ENDOCRINE
Award Title: Genetic and environmental determinants of age-acquired skewed X-inactivation and escape from X-inactivation
Funder: Medical Research Council

Abstract: The fundamental aim of this project is to understand the role of genetics and the environment in age-acquired skewed X-inactivation and in regulating the expression of genes on Chromosome X in females.  This project will assay skewed X-inactivation in 4000 ageing female twins from the deeply-phenotyped TwinsUK cohort. We will investigate the relationship between skewing and environmental factors, and determine if skewing can act as a biomarker for healthy ageing or disease prediction. Age-acquired skewing is heritable - we will utilize three strategies to explore its genetic basis. Classical twin modeling will be used to identify Gene x Environment interactions on the heritability of skewing.  We will perform a GWAS in 4000 twins to identify individual loci associated with skewing. Genome-wide genetic correlation methods will be used to identify shared genetic architecture underlying skewing and autoimmune diseases or cancer.  This project will comprehensively investigate escape from X-inactivation by deeply sequencing chromosome X transcripts in autoimmune relevant cell-types obtained from 50 female twins and by re-purposing existing large multi-tissue and longitudinal 'omic datasets from up to 850 deeply phenotyped female twins. This will allow investigation of which genes escape X-inactivation, and importantly how escape varies across individuals, across twin pairs, across tissues and over time.   Identification of regulatory variants (eQTLs and splice eQTLs) have been critical to interpretation, and eventual translation, of GWAS signals. Most eQTL studies do not include Chromosome X, and those that do have not taken the skewed status of the individuals into account, which may bias eQTL tests. This project will identify eQTLs on Chromosome X in a large multi-tissue dataset after accounting for skewed X-inactivation, and use these eQTLs to interpret GWAS loci.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Genetic and molecular bases of defective tolerance induction in autoreactive B lymphocytes in systemic sclerosis
Funder: Versus Arthritis

Abstract: The presence of circulating antibodies is a hallmark of immune dysregulation in systemic sclerosis (SSc). These autoantibodies are detectable prior to disease onset, define disease subsets, predict distinctive pattern of organ involvement, response to treatment and prognoses. However, it is unclear how autoreactive B cells are generated, escape tolerance and promote SSc disease. Our recent studies have revealed evidence for defects in B cell tolerance induction in immature transitional SSc B cells. Using purpose-designed protocols, we have discovered that transitional B cells can be divided into 4 distinct phenotypic and functional subsets, T1, T2, T3 and CD27+B cells. The T1 and T2 subsets are distinguishable by their differential capacity to undergo tolerance by apoptosis or by anergy following the engagement of their BCR. The T3 subset displays anergic functional status. CD27+transitional B cells, in contrast, respond rapidly to T cell-independent stimuli by producing IL-10. These studies established a novel paradigm for the developmental pathway of human transitional B cell maturation and tolerance. Using the paradigm, we uncovered defective tolerance induction in T1 B cells in SSc patients that lead to the expansion of circulating autoreactive IL-6-producing B cells. In addition, transitional as well as mature SSc B cells showed a defect in differentiating to IL-10 producing B cells. This PhD proposal will explore the genetic and molecular bases of defective tolerance induction, IL-6 production and defect in IL-10 production by B cells in SSc. By carrying out single cell genetic profiling and analysing major signalling pathways, the study can provide fundamental information on the cause(s) of defects in tolerance induction, preferential differentiation to IL-6 production and diminished IL-10 production by B cells in SSc patients. The study can also revealmolecular signatures that distinguish transitional B cells destined to become pathogenic rather than regulatory B cells.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Genome engineering as an approach to identify crucial miRNA targets in cancer
Funder: Medical Research Council

Abstract: MicroRNAs (miRNAs) have a crucial role in cancer development and progression. During a particular cellular process, they act by base-pairing with the 3'UTR of hundred of mRNA targets to repress their protein translation. Notably, it has been elegantly demonstrated that in Caenorhabditis elegans, the let-7 miRNA does not function to reduce gene expression noise broadly but to directs vulva development through regulation of a single target. Whether this mode of miRNA regulation also occurs in other systems, such as human, remains largely unclear. Prediction of miRNA targets, experimental validation and rescue experiments have suggested that this could be the case, but this has never been addressed systematically. Considering that a single miRNA can regulate thousands of transcripts, using this method to precisely address this question, for any single putative target, would be very time consuming. Herein, we aim to develop CRISPR-CAS9 pooled screening technologies that specifically and rapidly address this important biological question. The discovery of key targets of important miRNAs in cancer or other diseases can reveal new therapeutic targets/biomarkers. This proposed work follows from our recent study pending revision, in Nature Communication, where we discovered that two miRNAs, miR-100 and miR-125b, are induced by TGFb in advanced PDAC and are important effectors of the tumourigenic TGFb response. We developed a novel method to identify all the targets of these miRNAs, that we called RIP-USE, which indicated that these two miRNAs co-regulate hundreds of transcripts after TGFb induction, but could not identify the key targets of such miRNAs. Therefore, we now want to develop a series of CRISPR/CAS9 screening methods that would permit to identify the crucial miRNA targets. We will focus on the oncogenic miR-100 and miR125b as well the tumour suppressor miR-205 and miR-203 to develop methods that can be used to discover key miRNA targets for any miRNA of choice.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Geographies of exclusion and inclusion: A comparative investigation of families
Funder: The Health Foundation

Abstract: Although there is a clear link between young people’s mental health and the emotional support they receive from their families, there are currently gaps in the evidence on how this support can lead to positive or negative mental health outcomes, and the impact of wider social and economic factors.

This project run by the University of York aims to unpack how social and economic factors shape a family’s capacity to mobilise, consolidate and redistribute the necessary resources (financial, emotional and caring) to protect its younger members.

The project will focus on the perspectives and experiences of people aged 16–25 years in two communities in North Yorkshire: a rural coastal area experiencing social and economic deprivation (Scarborough) and a more affluent urban community (City of York).

The research design will ensure that differences in socio-economic status, as well as gender and ethnicity, are equally represented across both localities. It will compare how economic, social, cultural and environmental factors intersect with differing spatial contexts, and how these contexts shape families’ abilities to provide emotional support to young people.

The project will use qualitative and participatory arts-based methods, including interviews with young people, focus groups with agencies that support young people and arts-based participatory workshops. The project will also recruit young people from youth-led organisations as co-researchers, giving ‘voice’ to young people who are often marginalised from the mechanisms that shape policy and practice.

Integrating analysis of place-based inequalities with a more holistic perspective of the family will contribute to addressing research gaps and help with the development of local policies, especially those aimed widening health inequalities in North Yorkshire.


Research Activity Codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Geostatistical design and analysis of randomised evaluations with a geographic basis
Funder: Medical Research Council

Abstract: This project will develop methods for the design and analysis of randomised trials with a geographical basis - studies that include individuals on the basis of their location and where an intervention has a specific location. Cluster randomised trials are the most common method of evaluations for these studies. Spatial effects are typically ignored in these designs: neither spatial correlation nor spatially varying intervention effects are considered. This can lead to inefficient cluster design, treatment effects that vary arbitrarily with cluster design, and the inefficient sampling of participants, among other problems. We will develop and evaluate methods for the design and analysis of cluster trials that explicitly account for spatial effects and develop and assess a novel study design in which intervention locations are randomised across a continuous area.   WP1 will adapt geostatistical models to the cluster randomised trial and develop methods for treatment effect estimation, power and sample size analysis, cluster design, and approaches to contamination. We will evaluate the methods using simulated data. WP2 will extend the methods of WP1 to develop the "spatial trial" design in which interventions are randomly located or randomised to fixed locations or to a specific sequence of locations over time. We will document the different variations of spatial trial design and examine power and sample size, treatment effect estimators, restricted randomisation schemes, and efficient sampling methods. We will evaluate the methods using simulated data. WP3 will develop a software package implementing the methods with accompanying documentation for public release. WP4 will re-analyse a cluster trial of a sanitation intervention in urban and rural areas. We will also work with academic and implementation partners to provide training in these methods and develop proposals for trials using these methods.


Research Activity Codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Global Sanitation Technology
Funder: Royal Academy of Engineering

Abstract: Using robust approaches to designing, testing, and implementing novel onsite sanitation technologies and processes, this research aims to address engineering challenges associated with achieving the UN Sustainable Development Goal of universal access to safely managed sanitation. Examples will include more affordable, easier-to-assemble septic tank designs and modular methods to treat faecal sludge in rapidly urbanising cities and emergency settings. His approach combines laboratory experiments, fieldwork, mathematical modelling, and collaboration with in-country practitioners and end users to co-develop engineering solutions that will improve the lives of the poorest members of society in developing countries.


Research Activity Codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;3.3 NUTRITION AND CHEMOPREVENTION
Health Categories: GENERIC HEALTH RELEVANCE;ORAL AND GASTROINTESTINAL;INFECTION
Award Title: Good School Toolkit-Secondary Schools Pilot Trial
Funder: Medical Research Council

Abstract: The Good School Toolkit-Secondary School is a whole-school intervention to prevent physical, sexual and emotional violence against students, from school staff, peers, and within student intimate partnerships. We will conduct a phase 2 cluster randomised controlled trial with 2 arms and parallel assignment.  8 schools will be selected from a list of eligible schools in Kampala, stratified by faith/non-faith status and level of financial resources. Schools will be pair-matched and randomly allocated to receive the Toolkit plus usual care versus usual care and wait-listed to receive the Toolkit. The Toolkit will be implemented over 18 months. We will conduct a survey with all staff (about 200) and 960 randomly selected students in all 8 schools before randomisation, and again after the 18 month implementation.  Observations, qualitative focus groups discussions and individual interviews will be conducted with students, staff, administration, caregivers and key stakeholders throughout the 18 month implementation.  The main outcome of this phase 2 trial is whether criteria for progression to a phase 3 trial are met, defined as: >80% of staff and students reporting acceptability and >80% reporting understanding in endline survey; >3 of 4 intervention schools implementing with fidelity at endline; >6 of 8 schools agree to participate in the baseline survey; >6 of 8 schools participating in the baseline survey agree to be randomised, >6 of 8 of schools randomised agree to endline data collection; >70% of eligible students respond to surveys.  Findings from the research will be fed back to Raising Voices iteratively during the implementation period so that the intervention can be refined and optimised.  If a phase 3 trial is warranted, it would represent the first test of a whole school approach to prevent these multiple forms of violence in sub-Saharan Africa.


Research Activity Codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health Categories: INJURIES AND ACCIDENTS
Award Title: Green Walks: Healthy Ageing
Funder: Economic and Social Research Council

Abstract: The core aims of the project is to offer new functionality to navigation packages used world-wide, and to bring a new app to market, which focuses on prolonging good health as users age. 

In order to achieve these aims, Green Views is divided into two connected packages which: a) guide users to green spaces within walking distance of their front door; and b) encouraging older users to continue venture outside despite the challenges older age presents. More specifically, the project will pursue the following objectives:

A1: Generate a green-view database of an urban centre by extracting images from existing mapping platforms to calculate the amount of visible green space along roads 

A2: Develop a mapping system to generate circular walks of 10, 20, and 30 minutes from any starting point within the database. These walks will be optimized to take in the largest amount of green space possible

B1: Develop a web site collecting observations from walks in Norfolk. These raw observations will be refined into a creative-commons collection of things to look, listen, and smell for at particular times of the year. 

B2: Develop an iOS app which loads circular walks from Obj A2 and recommends observations from Obj B1 to seek out during the walk.

Lay Abstract: During and post Covid-19 lockdowns, the importance of access to green spaces for mental health has been highlighted. However, in the UK, we have deeply entrenched disparities in access to green spaces. A majority of care users over 64 and/or from non-white backgrounds do not believe they have local greenspaces within easy walking distance.

Green Walks will aid the UK population in finding greenspaces within easy walking distance of their homes, signposting environmental changes (such as flowers coming into bloom or local events) as incentive to get out of the house, and accompany care-users on their walks

The project will generate a green view database, using AI tools to extract images from existing mapping platforms to calculate the amount of visible green space along roads 

The team will co-design a web-based AI search interface and mobile app together with social prescribing link workers and end users to generate personalised walks to and from home, through areas with the highest green views

The app will use spatialised audio to guide the user along the walk, as well as providing social accompaniment, and quick access to help and/or companionship. It will  monitor the user's progress through GPS, motion data, and quick self-reported mental health cues. 

The project contains a citizen-science element allowing stakeholders to add areas of interest, areas to be avoided, community information, and incentives for care users to get out of the house and into green environments and will interpret data about use of the green spaces by other users.

Research Activity Codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Growing Old in the Soviet Union, 1945-1991
Funder: Wellcome Trust

Abstract: Research produced by the project will provide historians and gerontologists with access to a rich body of work that sheds light on hitherto unknown experiences of ageing in the Soviet Union - the world's first socialist state. This will be achieved by conducting extensive research over a 4-year period on: 1) state policies and attitudes to providing healthcare for older adults; 2) individual and collective experiences of ageing; and 3) the influence of gerontology on domestic and international politics. The project will change how historians consider the role of older adults in the Soviet Union after World War Two. Although scholars have probed issues of identity, trauma, and the meaning of life under late socialism, the role of elderly people has been largely overlooked, in spite of the ageing revolutionary vanguard. A focus on the period 1945-1991 will establish older adults and ageing as an integral part of the post-war narrative of Soviet history, and will make a distinctive contribution to current debates about ageing societies. Knowing what it was like to grow old in the Soviet Union will help historians relate debates about ageing and gerontology to political developments in international relations, healthcare, science, and welfare.

Lay Abstract: This project is the first to comprehensively examine ageing in the Soviet Union, 1945-1991. In the 1960s and 1970s the Soviet government was confronted with the problem of an ageing population and as a result state interest in the field of gerontology (the study of ageing) expanded immensely. The project first examines state approaches to ageing that include scientific research, healthcare policy, medical services, and psychiatry. Second, it explores more subjective aspects of ageing by finding out what it was like growing old in the world's first socialist society. The final aspect of the project focuses on the influence of gerontology in the Soviet Union and abroad through a study of the Institute of Gerontology in Kiev. This holistic approach to examining ageing will provide scholars with an important blueprint for the study of ageing societies in history and contribute to how people and societies understand the ageing experience.

Research Activity Codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health Categories: GENERIC HEALTH RELEVANCE