NIHRDataInsights/HRCSData huggingface dataset:
Title: Exploiting novel technologies to identify respiratory pathogens and characterise bacterial interactions in patients with cystic fibrosis.
Funder: Medical Research Foundation

Abstract: Cystic fibrosis (CF) is a genetically inherited disease requiring complex treatment and leaving patients susceptible to lung infections with bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus. Chronic airway infection with the P. aeruginosa remains the commonest cause of death and there is a link between earlier establishment of P. aeruginosa infection and a worsened clinical outcome. If P. aeruginosa is detected early enough, it can be cleared by using aggressive antimicrobial treatment. This window of opportunity is crucial because, once established as a chronic infection, bacteria like P. aeruginosa are impossible to eradicate, at which point life-long suppressive therapy is required. This represents a considerable treatment burden for patients and a significant cost for the NHS. Hence, diagnostics to identify early infection play a key role in the management of people with CF. Our work and other studies, has demonstrated that the upper airways are important in the initial stages of bacterial infection. Our hypothesis is that the upper respiratory tract is a key site for initial infection and that nasal swabs could therefore be used as an additional sample for the earlier detection of bacterial pathogens. In addition, the use of new sequencing technology (portable Nanopore sequencing) could significantly reduce the time to result from samples such as respiratory swabs and sputum samples. This combination of nasal swabbing as an early diagnostic tool and rapid sequencing for the identification of bacteria offers the potential for a prolonged and better targeted window for antibiotic therapy. This would have real impact at a life-changing point in the long term disease management and outlook of these patients. In addition to known pathogens, the CF lung can support a diverse microbial population. There is a poor understanding of the antimicrobial resistance potential of the entire microbial population and the impact of this on patients. Although limited evidence suggests that microbes in the lungs can interact and potentially alter the pathogenesis of other bacteria, further study in this area is needed.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CONGENITAL DISORDERS
Title: Investigating the role of cardiolipin metabolism in mitochondrial DNA replication and mitochondrial division
Funder: Medical Research Council

Abstract: Mitochondria are fundamental organelles in cellular metabolism. They provide the major source of energy in human cells and control numerous biochemical and signalling pathways. Mutations in nuclear- and mitochondrial DNA (mtDNA)-encoded genes lead to a variety of untreatable diseases. The UK adult prevalence is 1 in 4,300, ranking mitochondrial diseases among the most commonly-inherited neurological disorders. One emerging category of mitochondrial diseases relates to impaired phospholipid (PL) metabolism. Cardiolipin (CL) is a non-bilayer PL, found only in mitochondrial membranes, with numerous essential mitochondrial functions. Mammalian CL biosynthesis is a complex process that involves the endoplasmic reticulum (ER) and mitochondria, but it is ultimately synthesised from phosphatidic acid (PA) within the inner mitochondrial membrane (IMM). Crucial for the transfer of PA from the ER to the IMM is the TRIAP1-PRELID1 complex. Further evidence of the intrinsic connection between the ER and mitochondria has recently emerged with evidence that mtDNA replication occurs at ER-mitochondria contact sites, thus coupling mtDNA synthesis and mitochondrial division. However, the precise mechanism of this process and impact perturbed ER-mitochondria contact sites have on mtDNA replication remains poorly understood. I have identified the first pathogenic mutations (resulting in frameshift of the protein) in TRIAP1, encoding a protein essential for CL biosynthesis, in a patient with mitochondrial disease. I have confirmed impaired CL metabolism and aberrant mtDNA replication in both patient-derived fibroblasts and muscle. This new discovery supports the role of PL homeostasis in mtDNA maintenance and presents an opportunity to advance understanding of fundamental aspects of mitochondrial biology. The overarching research aim of this fellowship is to gain a deeper understanding of how CL metabolism influences mtDNA replication and mitochondrial division.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Identifying genetic and environmental risk factors for cleft using genome wide association study data
Funder: Medical Research Council

Abstract: Approximately 1 in every 650 children born in the UK each year will have an orofacial cleft. The Cleft Collective (CC) is a set of cohort studies of children born with a cleft across the UK and their families set up in 2012 which to date has recruited over 2500 families. In addition, a similar family study including around 1000 families has been recruited in Bonn Germany. Both studies have banks of biological samples (blood, cleft tissue or saliva) collected from participants and the CC has funding to genotype participants using a genome wide association study chip. The aim of this project is to genotype the Bonn sample using the same chip as the CC and use data from both studies to carry-out genome wide association studies (GWAS) to determine whether there are further common variants (not so far detected) associated with cleft lip and/or cleft palate. We will carry-out GWAS by cleft subtypes to look for subtype-specific genetic variants, carry-out a GWAS of mothers of children born with a cleft to determine whether there are maternal genetic variants that increase the risk of having a child with a cleft and investigate parent-child gene interactions in cleft. In order to identify non-genetic modifiable risk factors for cleft we will carry-out two sample hypothesis-driven and hypothesis-free Mendelian randomization using GWAS data from mothers to determine whether exposures in pregnancy are likely to cause cleft. This is an analytical technique pioneered and advanced by researchers at the University of Bristol, which uses genetic variants as surrogates for environmental exposures to overcome problems of confounding, measurement error and reverse causation which are inherent in observation studies. The analyses listed above will allow us to identify the causes of cleft, and determine subtype specific risk factors, and inform public health policy to reduce the occurrence of cleft.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CONGENITAL DISORDERS
Title: Can precise re-creations of disease gene variants be made in Xenopus that are useful to inform clinical interventions?
Funder: Medical Research Council

Abstract: Next generation DNA sequencing (NGS) has revolutionised our understanding and mitigation of human genetic diseases by enabling clinical research to identify causal variants within a gene. NGS has produced many successes in the unambiguous identification of disease-causing gene variants that have directed effective interventions for patients and their families. A challenge in making use of this sequence data is however interpretation of variants of uncertain significance (VUS). For around half of patients, the link between the gene(s) identified by sequence comparisons and their disease is insufficiently robust for clinical decision making. Assessing VUS function needs rapid ways to test variant pathogenicity. While non-animal studies can be informative, they do not reflect the complex interactions in organisms. The main approach uses mouse models but, due to the financial and ethical costs involved, alternatives are sought. Highly efficient gene editing is routine in Xenopus frogs and analysis of resulting phenotypic changes is very efficient; tadpoles are transparent, fluorescently-labelled transgenic lines are available and there is robust microCT analysis. Collaborating between clinical and research staff, we will re-create prioritsed VUS from patients. As proof of principle we made and analysed 10 disease-related gene changes in X. tropicalis, producing phenotypes very similar to the patients in 9 of them. To produce data robust enough for clinical use it is necessary to make highly specific mutations in the appropriate zygosity. Homology-directed repair works very efficiently in frog oocytes with up to 75% correct insertion reported and we have overcome the bottleneck in this technique. By using this together with lssDNA injection in embryos, we will precisely re-create a variety of patient VUS in frogs and work collaboratively to understand how effective these are at informing both clinical judgements and mechanistic processes of rare diseases.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CONGENITAL DISORDERS
Title: Investigating the role of arginine methylation as a critical regulator of DNA replication and genome stability
Funder: Medical Research Council

Abstract: Replication stress (RS) is a term that encompasses any type of abnormality that obstructs replication. It is becoming increasingly evident that RS is an important pathological process underpinning the development of human disease. It is thought that the DNA damage caused by incomplete replication leads to increased cell death, particularly in highly proliferative tissues. This is exemplified by Microcephalic Primordial Dwarfism (MPD), which is a genetically heterogenous group of disorders characterised by severe microcephaly, growth retardation and a significantly reduced life expectancy. Whole exome sequencing of MPD patients has identified a common underlying defect in pathways required to maintain genome stability, notably DSB repair and DNA replication. As such, the study of microcephalic disorders and the cellular pathways affected in cells from these patients has significantly furthered our understanding of the molecular mechanisms that have evolved to protect against the deleterious effects of RS. Several years ago, our laboratory identified DONSON as a novel replication factor mutated in patients with MPD. Whilst we demonstrated that DONSON is essential for stabilising a subset of replication forks, in part through its ability to activate ATR, the precise function of this protein and how it is regulated is unknown. Recently, we have demonstrated that DONSON is arginine methylated and that this is essential for unperturbed DNA synthesis. Based on this, we postulate that arginine methylation is a critical regulator of DNA replication. Therefore, this proposal aims to investigate how arginine methylation of DONSON regulates DNA replication and the ATR-dependent replication stress response. From this, our goal is that data generated will not only advance our fundamental knowledge about the post-translational regulation of DNA replication but it will also further our understanding of the mechanisms underlying the development of microcephalic disorders.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CONGENITAL DISORDERS
Title: Role of inflammation on craniofacial morphogenesis
Funder: Medical Research Council

Abstract: Cephalic neural crest is a highly migratory embryonic cell population that colonizes and originates most of the face of humans and other vertebrates. Therefore, any problem in their migration can have devastating consequences, leading to craniofacial malformations. Some of the most common craniofacial malformations are oral clefts, such as lip and palate clefts. Epidemiological and genetic evidence lead us to propose the idea that oral clefts are generated by an inflammatory response triggered in the cephalic neural crest. It has been shown that inflammation in gastric cancers leads to down regulation of E-cadherin by triggering hypermethylation of its promoter. This evidence together with our preliminary data allow us to propose the hypothesis that a pro-inflammatory response in the neural crest impairs its migration by inhibiting E-cadherin expression. To test this hypothesis, we will answer the following questions: 1a. Does inflammation inhibit cephalic neural crest migration? 1b. What is the cellular behaviour affected by inflammation during neural crest migration? 2a. Is E-cadherin required in the neural crest for its migration? 2b. Which cell behaviour is controlled by E-cadherin during neural crest migration? 3a. What is the molecular mechanism by which inflammation inhibits E-cadherin expression during neural crest migration? 3b. Is an intrinsic basal pro-inflammatory response required for normal neural crest migration? This project will demonstrate for the first time the role of inflammation and E-cadherin on cephalic neural crest migration and will identify the mechanism by which inflammation controls E-cadherin expression. The results of this project will have a high impact in understanding and generating new diagnostics and preventive strategies for oral cleft malformations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CONGENITAL DISORDERS
Title: Congenital Anomalies - Patient-led Functional Genomics
Funder: Medical Research Council

Abstract: This cluster will generate and study mouse models of prioritized gene variants identified from patients with congenital anomalies, focusing on anomalies affecting the cranial, neural, heart and kidney structures. We will use genome engineering to mimic the human gene variants in mouse models, in order to assess the overall functional consequence of pathogenic mutations. The cluster will analyze and distribute these mutants, determine underlying causes, and collaborate with clinicians. A key objective is bringing together diverse experts studying syndromic disorders, as many genetic disorders affect multiple organ systems. A second objective is to improve live monitoring of animals in early life, which will improve our ability to link gene variation to function in structural malformations. The overall goal is to enhance UK expertise in determining causes, understanding mechanisms and identifying potential therapies for congenital anomalies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CONGENITAL DISORDERS
Title: SonoSpeech Cleft Pilot: A Pilot Randomised Control Trial of Ultrasound Visual Biofeedback Versus Standard Intervention for Children With Cleft Lip and Palate.
Funder: Chief Scientist Office, Scotland

Abstract: Children with cleft lip and palate can continue to have problems producing clear speech after surgery. This can lead to social, emotional, and educational challenges. Treatment involves teaching children the correct tongue movements to produce speech sounds. This is known as articulation intervention. However, this intervention is challenging because the tongue is hidden from view and movements are difficult to see and describe. This project will try a new treatment, ultrasound visual biofeedback. In this treatment an ultrasound scanner similar to that used to image babies in the womb, is placed under the chin allowing children to see their tongue movements in real-time. The Speech and Language Therapist helps the child to use this real-time dynamic information to change their tongue movements. Ultrasound Visual Biofeedback has already been used successfully with children with other types of speech disorders and with children with Cleft Lip and Palate to measure the severity of the speech disorder. In this study children with Cleft Lip and Palate will be randomly assigned to either U-VBF or articulation intervention. We will measure the children’s speech before, during, and after both interventions to determine how feasible and acceptable the treatment is to families and to plan for a larger study


Research activity codes: 6.7 PHYSICAL
Health categories: CONGENITAL DISORDERS
Title: The ATeam: Producing healthcare guidance for children with ataxia telangiectasia (A-T) including the exploration and design of a home-based exercise package
Funder: Action for A-T

Abstract: This project aims to produce healthcare guidance for children with ataxia telangiectasia (A-T) including the exploration and design of a home-based exercise package

Lay abstract: This project aims to provide the foundations for therapy research into ataxia telangiectasia (A-T). A large team of parents, academics and clinicians who are interested in A-T research have been formed called the ATeam. This team will work alongside and support a PhD student, Munira Khan, in reviewing the existing research around A-T therapy management (i.e. nurses and allied health professional therapy management of A-T) and summarise these findings. These findings will help inform guidelines for A-T therapy management for nurses and allied health professionals. Findings from this literature review will be shared with A-T specialist centres to be considered for the next edition of the A-T guidelines when they are reviewed. The team then plan to develop a child and parent held set of notes, to help monitor the child’s experience with A-T and share this resource with health professionals and researchers, if required. The third activity of the project will be to develop a home-based programme of exercises with an interactive group element. To explore how feasible, it is to do something at home that could target improvement of ataxia or other priority A-T problems that children experience, such as recurrent chest infections. This stage of the research will hopefully lead onto a larger research trial to properly explore how effective the home-based programme is for children with A-T.

Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CONGENITAL DISORDERS
Title: Modulation of RELB/p52-dependent NF-κB activities to improve neurodegenerative symptoms of AT
Funder: Ataxia-Telangiectasia Society

Abstract: Modulation of RELB/p52- dependent NF-KB activities to improve neurodegenerative symptoms of A-T

Lay abstract: Ataxia Telangiectasia (A-T) is a rare inherited disorder caused by mutations in the ATM protein. The most devastating symptom of A-T is neurodegeneration linked with the progressive loss of neurons in the brain. There are currently no treatments for individuals with A-T. Using human cell models of A-T, we discovered that microglia, a specific cell type of the brain, exhibit an abnormal behaviour that contributes to neurodegeneration. One of the functions of microglia in a healthy brain is to remove dead or damaged neurons and other cells by engulfing them. We find that A-T microglia abnormally take up healthy neurons, contributing to slow progressive loss of neurons. The defects in microglial behaviour in A-T are caused by damage of our genetic material due to loss of ATM protein. We propose to investigate the molecular mechanisms of microglial misbehaviour in A-T. These studies will broaden our understanding of the disease and will allow us to propose and test possible treatments to mitigate neurological symptoms of A-T.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: UK CF Innovation Hub - Workstreams 1-3 , Phase 2 - Cambridge
Funder: Cystic Fibrosis Trust

Abstract: The focus of the Innovation Hub based at the University of Cambridge will be in the area of lung health. Over the 5 years, the Innovation Hub will lead research to keep lungs healthy.

Lay abstract: Funding for the Cambridge Innovation Hub - https://www.cysticfibrosis.org.uk/the-work-we-do/research/where-your-money-goes/how-we-invest-in-research/innovation-hub

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CONGENITAL DISORDERS
Title: Development of an in vitro model to dissect the mechanism of fungal persistence in the cystic fibrosis (CF) lung
Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research

Abstract: Cystic fibrosis is the most common fatal genetically inherited disease in Caucasian populations.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CONGENITAL DISORDERS
Title: Antisense Oligonucleotides for the Treatment of Rare Genetic Disorders in the Arab World
Funder: The Academy of Medical Sciences

Abstract: The pathogenesis of most of the rare genetic disease-causing mutations is poorly understood. Therefore, there is a need for identifying the genetic disease variants and provide the basis for understanding disease progression. The need for early diagnosis and better therapeutic strategies is not only an important issue for scientists and physicians but also a crucial concern from an economic perspective. Nowadays, Patient-specific cell lines can provide a window for testing the efficacy of gene or drug-based therapies; elucidate previously unknown mechanisms and pathways of disease. Although next-generation sequencing is revolutionizing the diagnosis of rare genetically-acquired diseases, the limited number of patients affected by each rare disease present a major challenge for drug development. The last decade has shown a success in antisense oligonucleotides (ASOs) use for the treatment of neuromuscular diseases. ASOs are short, typically 8–50 nucleotides in length, synthetic, single-stranded oligodeoxynucleotides, which bound by Watson-Crick complementary base pairing to a target mRNA and lead to endonuclease-mediated transcript knockdown and, consequently, to reduction of the protein levels. Currently, three ASOs have received approval by the FDA for the therapy of neurological disorders. These are nusinersen for spinal muscular atrophy (SMA), eteplirsen for Duchenne muscular dystrophy (DMD), and inotersen for the treatment of amyloidosis attributed to mutations in the transthyretin protein. Other ASOs are in preclinical development or in clinical trials for a number of disorders. This fellowship will focus on ASO development for rare genetic disorders with identified disease-causing variants. ASOs will be designed to target novel genetic mutations and disease modelling will be applied to study the disease mechanisms. Our approach will establish the foundation for a personalized medicine-based gene therapies to rescue significant disease-associated genetic abnormalities and to screen potential innovative ASOs-based therapeutic drugs. To the best of our knowledge, this study is the first to propose ASOs development for studying rare diseases on patients from Jordan and the Middle East. This work will engage the communication by developing collaborations between Jordanian universities (University of Jordan) and other international universities (University of Oxford). The contribution of Jordanian universities on establishing such technologies would result in significant investment in the next few years for Jordan in the field of gene therapy and personalized medicine.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS