NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Aneuploidy is a driver of childhood cancer and a target for novel therapies (co-funded by Children with Cancer UK)
Funder: Cancer Research UK

Abstract: Background.

Across the spectrum of childhood cancer therapies, targeting of gene-specific aberrations is being developed to replace current conventional treatments, which although effective, are highly toxic. Non-random whole chromosome aneuploidies are frequent across all childhood cancers and although some aneuploidies and ploidy shifts are established prognostic markers, they rarely co-occur with clinically actionable gene-specific aberrations. Currently there are no therapies designed specifically to counteract the combined effects of multiple cancer driver genes located across intact gained chromosomes.

Hypotheses.

We hypothesise that (1) common underlying mechanisms drive the formation of aneuploidies across many childhood cancer types; (2) cells attaining the appropriate combination of chromosomal imbalances resulting from aneuploidy will achieve the required level of fitness to propagate and progress to cancer; and (3) that among the gained chromosomes, specific aneuploidy-associated genes orchestrate oncogenic pathways.

Methods.

Within the Newcastle University Centre for Cancer, we have longstanding expertise in the genetic study of childhood cancer, particularly in acute leukaemia and medulloblastoma. The integration of expertise in chromosome biology and cell division into this project introduces innovative functional cell biology approaches not previously applied to this cancer field. Ground-breaking models of aneuploidy-driven cancer will be created with human artificial chromosomes (HAC) expressing multiple oncogenes.

Aims.

Our specific aims are: 

(i) to identify those predisposing genetic factors leading to aneuploidy, 

(ii) to understand the underlying mechanisms driving the formation of the specific aneuploidies and their contribution to cancer development and 

(iii) to identify those genes located on the gained chromosomes, which are driving cancer, using genomic, transcriptomic and CRISPR screening data combined with HAC model based positive selection screens.

Results will achieve.

Understanding of predisposing factors and the mechanisms underlying aneuploidies in this project has potential to further improve risk stratification and early disease detection and may also lead to development of preventative measures. Identification of oncogenes and associated pathways will be key to the discovery of novel therapeutic targets applicable to a high proportion of aneuploidy driven cancers. The novel techniques established will also be applicable to the analysis of aneuploidy involving other chromosomes and malignancies. We are confident that, together, our team’s multi-disciplinary approach can identify novel targets and reduce toxicity related to conventional chemotherapies within these childhood cancers.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Antimicrobial Stewardship in Hospitals, Resistance Selection and Transfer in a One Health Context
Funder: Medical Research Council

Abstract: The " Antimicrobial Stewardship in Hospitals, Resistance Selection and Transfer in a One Health Context" (STRESST) project aims to determine the effects of hospital wide antimicrobial stewardship implementation on the levels of antibiotic residues and antimicrobial resistant bacteria leaving the hospital via wastewater. The point of collection of the wastewater will be on the perimeter of the hospital and will represent the boundary between the hospital environment and the wider environment. Once this data has been obtained it will be used to determine the effects on intracellular transposition and intercellular conjugation using state of the art molecular tools and fermenter systems which will enable us to model the chicken caecum. The work will be carried out in five interlinked work packages as follows; 1) hospital wide antimicrobial stewardship implementation at the Queen Elizabeth Central Hospital in Malawi, 2) hospital wastewater sampling before and during antimicrobial stewardship implementation. This will be carried out using bespoke auto-samplers leading to retrieval of the microbiology and determination of concentrations of antibiotic residues. 3) Microbiological and genomic analysis of both susceptible and resistant bacteria to reveal the levels of different antibiotics and antibiotic resistance genes present within the sampled bacteria and 4) conjugation assays to determine the effects of antibiotic residues on intercellular transfer of AMR genes and finally 5) transposition assays to determine the effects of antibiotic residues on intracellular of AMR genes between replicons in the same cell. At the end of the project we will be in a position to demonstrate the effects on AMR downstream of a hospital where robust antimicrobial stewardship interventions have been successfully implemented and highlight hospital wastewater as a site for future engineering solutions to completely remove antibiotic residues.


Research Activity Codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION
Award Title: Assessing and optimising the ‘forgiveness’ of tuberculosis drugs for non-adherence to treatment: an interdisciplinary project using pharmacodynamic modelling and wet laboratory approaches
Funder: Wellcome Trust

Abstract: Tuberculosis is a bacterial disease that affects 10 million people per year globally, with an associated 1.4 million deaths (2019). Current tuberculosis treatment plans are lengthy (minimum of six months) and have extensive side effects, resulting in patients not taking drug doses.  The impact of missing doses on success of a patient’s treatment are poorly known. This is dependent on a treatment drug’s ability to ‘forgive’ (i.e. be robust to) missed doses, which is a function of how long a drug is in the body for and stays at a level where it is working. Recently, new digital technologies that monitor patients have started to give us detailed information about how precisely patients take, or miss, doses of their treatment. This allows us to investigate how these drug taking patterns are affecting patient outcomes. I aim to explore how real-world dose-taking affects the performance of rifampicin, an anti-tuberculosis drug. I will do this by adapting an existing mathematical model, including improving its ability to model how missing doses affects how the bacteria grows through laboratory experiments. I will use the model to assess the impact of missing doses on the performance of rifampicin and whether this could be improved.


Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: INFECTION
Award Title: AstraZeneca Secondment for Clinical Pharmacology Training
Funder: Medical Research Council

Abstract: The aim of this secondment is to promote knowledge exchange between clinical teams in the NHS, academia and biopharmaceutical sector via cross-sector engagement on early phase clinical trial activity. This will be achieved through a 9-month secondment of a Specialty Training Registrar in Clinical Pharmacology and Therapeutics from Addenbrooke's Hospital into the clinical project team for a Phase 1 or Phase 2a study within the Cardiovascular, Renal and Metabolic group at AstraZeneca (AZ). The secondment will focus on a Phase 2 cirrhosis study with Zibotentan (an endothelin antagonist), in combination with dapagliflozin, in patients with portal hypertension or cirrhosis, an area of unmet clinical need. The secondment will provide training for the secondee in key components of the core syllabus for Clinical Pharmacology, a discipline where there is a national skills shortage. Direct exposure to multiple aspects of the drug development pipeline will also provide a deep understanding of industry drivers in the development of a competitive molecule. In parallel, as a study physician, the secondee will bring significant research exposure, clinical acumen and a specific interest in renal disease which will be valuable to AZ in the context of renal aspects of cardiovascular and hepatic drug development.  Overall, this secondment will benefit all parties by promoting transfer of knowledge between sectors. Through direct exposure to the biopharmaceutical industry, it creates an opportunity for the secondee to enhance their professional skills, knowledge and network with opportunities for career development. By focusing on clinical pharmacology, the secondment will boost training in a specialty where there is a national skills shortage and AZ will benefit from the secondee's specialist clinical knowledge. Collectively, these factors align closely with the aims of the UKRI Innovation Scholars programme bringing a range of benefits to the wider biomedical sciences sector.


Research Activity Codes: 5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Auditory scene analysis in acoustic and electric hearing
Funder: Medical Research Council

Abstract: Auditory Scene Analysis (ASA) refers to the perceptual separation of competing sounds. Failure to separate sounds remains the major complaint of people with hearing loss, particularly those whose hearing has been restored by a cochlear implant (CI). We use a combination of behavioural and electrophysiological techniques to a) study the neural basis of ASA in normal-hearing listeners, b) investigate its modulation by cognitive processes such as attention and language processing, c) investigate why it is impaired by CI patients, and d) develop methods for improving ASA and other aspects of hearing by CI users.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: EAR;MENTAL HEALTH;NEUROLOGICAL
Award Title: BRAZZX - Developing a scalable and predictable fermentation process for Brazzein, a new, non-caloric protein sweetener
Funder: Innovate UK

Abstract: Calorie gluttony due to sugar over-consumption has led to a worldwide epidemic of obesity and diabetes. The recent statistics highlighting the high propensity of obese and diabetic individuals to require hospitalization and intensive care during COVID infection is a wakeup call for the world to tackle the sugar reduction agenda with renewed urgency.



Current non-caloric sweeteners have not met the aims of previous sugar reduction efforts. This is primarily due to the unfavourable sweet taste profile of most of these sweeteners. Moreover, prolonged consumption of some artificial sweeteners has been shown to result in negative health consequences. Consumers demand a non-caloric sweetener that actually tastes like sugar and can be produced on a commercial scale. **Magellan is developing Brazzein as the next generation of non-caloric, natural sweeteners to overcome the limitations of currently available alternatives.**



Brazzein is a natural protein molecule that is found in a rare West African fruit and has been consumed by humans and primates for centuries. The sweet taste quality of Brazzein is remarkably similar to tabletop sugar. Moreover, being 1500x sweeter than sugar, one would need to use very little of this sweetener in beverages and food, resulting in negligible calories being consumed.



Magellan is developing a scalable and cost effective manufacturing platform for this remarkable natural molecule in order to advance the war against sugar.


Research Activity Codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health Categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE;STROKE
Award Title: BactiVac
Funder: Medical Research Council

Abstract: Bacterial infections are major contributors to the global burden of disease among humans and animals in LMICs, hampering development. They are particularly problematic where diagnostic facilities are lacking, and treatments are increasingly compromised by the scourge of antimicrobial resistance. Prevention through vaccination is an efficient and cost-effective strategy, but for many bacterial infections, no suitable vaccine is available. A network that champions bacterial vaccinology has the transforming potential to advance bacterial vaccines for LMICs, save lives and promote economic growth. Such a network does not currently exist and is needed now. The network will complement the active and strong support already present for viral outbreak pathogens through the 'UK Vaccines Network' and WHO 'R&D Roadmap' and 'CEPI' initiatives. BactiVac seeks to redress the current imbalance in global vaccinology, with its vision to facilitate end-to-end LMIC human and animal bacterial vaccine development. It will focus on the transition of promising vaccines from preclinical studies to clinical trials, where many flounder. Bringing together diverse parties with expertise in complementary aspects of bacterial vaccinology and a strong emphasis on LMIC and industry involvement, will help galvanise the community, foster new partnership and disseminate key relevant information. This will be supported by a members directory, website, newsfeeds and annual meetings. Two landscape scoping exercises will assess LMIC priority bacterial diseases for vaccine development and industrial capacities to support translation and clinical development of these vaccines. Catalyst funding will support innovative bacterial vaccine R&D projects and partnerships, and training opportunities to transfer vaccinology skills to LMICs. The network will serves as a global voice for bacterial vaccinology through advocacy initiatives targeting ministries of health and global health policy makers and funders.


Research Activity Codes: 3.4 VACCINES
Health Categories: INFECTION
Award Title: Balancing co-stimulatory versus co-inhibitory receptors to control the function of Tregs in autoimmunity
Funder: Versus Arthritis

Abstract: CD4+FOXP3+ Regulatory T cells (Tregs) are crucial for maintaining immune tolerance. However, we still do not fully understand how they keep the immune system in check, or why they fail to function in autoimmune diseases, such as juvenile idiopathic arthritis (JIA). Although modern therapies have improved outcomes in autoimmunity, they are not always effective and often come with severe side effects. A better understanding of how Tregs are altered in autoimmunity will lead to better therapies.

T cell activity is dependent on co-receptors, and targeting specific co-receptors is a successful approach for immunotherapy. In preliminary studies I found that Tregs in JIA synovial fluid (SF) express high levels of co-receptors, and that the microenvironment is rich in their ligands. Thus, I hypothesize that altered co-receptor signalling in Tregs could contribute to their dysfunction in autoimmunity.

My research will focus on the co-receptor pair CD226 and TIGIT: two co-receptors highly expressed on Tregs but with poorly characterized function in these cells. I will establish signalling, receptor-receptor and receptor-ligand interaction models and study their effects on Treg function. I will generate T cell and Treg lines with specific knockout (CRISPR-Cas) and overexpression (lentiviral) of CD226 and/or TIGIT to delineate receptor-specific roles. I will assess whether Treg signalling via CD226 and TIGIT is altered in autoimmunity by utilizing SF samples from inflamed JIA joints. Additionally, I will assess the impact of mutations in the CD226/TIGIT pathway, or accessory molecules, found in primary immunodeficiencies (PIDs) presenting with autoimmune features. Lastly, I will test whether modulating the CD226/TIGIT pathway in patient-derived Tregs is a suitable therapeutic approach to restore immune-balance in autoimmunity.

Determining how Treg function is controlled by co-receptors will increase our understanding of immune tolerance and may lead to new drug targets for JIA and other autoimmune conditions.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Bayesian Network Decision Support in managing low back pain: Development, exploration & feasibility
Funder: Barts Charity

Abstract: Low back pain (LBP) is common costing the economy £12 billion per year. LBP is also complex to assess, rendering treatment decisions complicated, even for expert clinicians. Delayed care, undesirable pathway variation and sub-optimal outcomes are common. In pre-doctoral work, I developed a promising Intelligent Care Decision System (ICDS), incorporating artificial intelligence, to detect serious spinal pathology. I will further investigate the use of an ICDS to support assessment decision for all LBP based on evidence and clinical reasoning that is then trained by LBP treatment outcomes. In three work programmes, I would: consult patients and clinicians about optimal pathway integration of an ICDS; further develop the ICDS by encoding best practice in a leading spinal triage service; and carry out feasibility studies. Success would yield a tool suitable to improve decision making for LBP by non- experts in the range of digital solutions increasingly being used in out-patient care.


Research Activity Codes: 7.3 MANAGEMENT AND DECISION MAKING
Health Categories: NEUROLOGICAL;MUSCULOSKELETAL
Award Title: Beyond the pol II CTD: the expanding roles of the pol II CTD modification enzymes
Funder: Wellcome Trust

Abstract: The multiple Tyr1Ser2Pro3Thr4Ser5Pro6Ser7 repeats within the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase II (pol II) undergo reversible phosphorylation during transcription of human protein-coding genes1. The pattern of CTD phosphorylation is controlled by CTD kinases and phosphatases through the transcription cycle, which ensures the sequential recruitment of transcription and RNA processing factors required for correct gene expression.
 
It is now becoming clear that the "CTD" modification enzymes have multiple additional targets that may play key roles in transcription, RNA processing and even translation. The exact roles that these kinases and phosphatases play in the cell is therefore not yet well understood. The aim of the proposed research is to understand the precise role(s) that CTD kinases and phosphatases play in transcription and downstream processes through modification of the CTD and other factors, what molecular mechanisms are involved and how their activities are co-ordinated. Towards this goal, I will use state of the art technology to determine the direct effect of loss of CTD kinase or CTD phosphatase activity, identify the targets of the CTD kinases and phosphatases and characterize the molecular interactions underlying the functions of CTD kinases and phosphatases.

Lay Abstract: The genes contained in our chromosomes direct the production of the components necessary for our cells to function correctly. This is known as ‘expression’ of the gene. To ensure that the appropriate products are made at the right time and in the right place, gene expression is regulated at many steps. Failure of these controls can result in disease. We are investigating the regulation of gene expression at several steps including the first step where the information contained in our genes is copied by a process known as transcription into RNA. We are also investigating what happens to the RNA during and after transcription. The molecular mechanisms controlling these process are not yet completely understood. My aim is to identify the proteins involved in these processes and determine their interactions. Defining the fundamental mechanisms regulating gene expression will help to fully understand the underlying causes of many diseases.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Award Title: BioGrOA: Imaging joint biomechanics in growth and osteoarthritis
Funder: Medical Research Council

Abstract: Osteoarthritis (OA), characterised by articular cartilage loss, affects almost 9 million people in the UK and is a major financial, social and healthcare burden. Advancing our understanding of the mechanisms underpinning disease aetiology will enable us to deliver new paradigms to identify those at risk of OA, and to deliver personalised interventions to treat patients with OA.  Our previous research has identified associations between growth plate cartilage phenotypes and OA development. Further, we have developed new synchrotron X-ray imaging technologies to allow determination of nanoscale mechanical strains in intact joints under loading. Here we will build on this work and for the first time will use a unique integration of approaches and resources in musculoskeletal biology, epidemiology, biomechanics and imaging to examine our hypothesis that: growth plate cartilage dynamics and joint biomechanical functionality are intimately linked. We will apply our new imaging methods to directly test our hypothesis in young, adult and aged OA-prone (STR/Ort mice) and healthy (CBA wild-type mice) intact joints. We will apply loads to murine knee joints and examine the subsequent strain patterns using our unique digital volume correlation code. We will then correlate these to hierarchical anatomical changes in joint structure, which we can now visualise at an unprecedented resolution. Next we will investigate the biomechanical and anatomical implications of microfractures in these joints. Finally, we will interrogate the MRC National Survey of health and development (NSHD) to determine if an association exists between the joint shape and life course longitudinal growth using previously derived measures of height size, tempo and velocity. This work has the potential to improve human health by identifying those at risk of osteoarthritis and by identifying associated imaging biomarkers that predict OA onset and progression.


Research Activity Codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: MUSCULOSKELETAL