NIHRDataInsights/HRCSData huggingface dataset:
Title: Genetic basis of craniofacial malformations.
Funder: Wellcome Trust

Abstract: Recent developments in analysis of DNA now make it possible to find the chemical sequence of the most important parts of our genetic makeup (the ~23,000 genes or exome ), in a single experiment lasting a few days. We want to exploit this new technology to help provide better diagnoses for patients who have malformations of the skull or face, and their families. In about 40% of cases we think that alterations in specific genes are responsible, but in about 40% of these, we still can't identify t he causative gene, despite a lot of previous research. We plan to use exome sequencing on DNA from 12 carefully chosen patients with craniofacial malformations. We will sift through the results looking for potential causative DNA changes, which we will then screen in a panel of several hundred samples from patients with related craniofacial malformations. We hope to establish a critical role for at least 4 new genes in craniofacial malformation during this work. This will immediately pave the wa y for better diagnostic tests for patients, and, by learning more about what the genes do, could eventually result in new treatments.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: CONGENITAL DISORDERS
Title: Investigation of the variant Tubulin alpha 8 in muscle and brain.
Funder: Wellcome Trust

Abstract: Tuba8 is a novel variant tubulin gene. We have recently identified mutations in this gene as a cause of severe mental and physical retardation. These children were unable to walk and profoundly weak. They all had a developmental brain abnormality, polymicrogyria. However in the course of investigation of the tuba8 gene we observed that the tuba8 protein localised very specifically to the Z lines in muscle. These structures are intimately involved in the transmission of tensile forces from muscle to surrounding tissues. Furthermore the time course of tuba8 expression is very different to that of other tubulins. Unlike tuba1a, tuba8 is not expressed until after myofibrils form and the muscles begin to twitch. The tubulin isoforms expressed by skeletal and cardiac muscle have not yet been fully characterised . The properties of Tuba8, an unusual and divergent isoform that is highly enriched in cardiac and skeletal muscle, have not been investigated at all. Our preliminary data suggest tha t this isoform has novel properties and that it may be involved in linking the MT network in muscle cells to structures at or close to the Z-line. Some of the weakness in affected children may be directly due to muscle abnormalities.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Nanoparticles for topical administration of siRNA to the airways for cystic fibrosis therapy
Funder: Wellcome Trust

Abstract: Cystic fibrosis (CF) is one of the most common inherited diseases. It affects several organs including liver and pancreas, but the most-life-threatening affects are on the lung. A relatively new genetic approach called RNA interference has therapeutic potential for CF. This involves small molecules called siRNA which can switch off genes in the targeted cell with a high degree of specificity. One of the big challenges is how to deliver siRNA to the lung? We believe nanoparticles offer a solutio n- effectively wrapping up the siRNA into nanoparticles about one ten thousandth of a millimetre in diameter. The best way to deliver therapeutics to the lung is in an inhalable aerosol, so we will assess delivering the nanoparticles in this way. We will then assess an siRNA, targeting a gene called ENaC in human CF cells, measuring the changes to asses restoration to normal values. In CF cells, ENaC is responsible for excessive uptake of water from the fluid on the cell surface which ultimately makes the lung fluids and mucus thicker and stickier. Switching off this gene could help to restore the cell physiology to normal parameters and restore the cell surface liquid layer to improve bacterial clearance.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CONGENITAL DISORDERS
Title: Mitochondria-targeted protective strategies for limiting injury in the developing brain.
Funder: Wellcome Trust

Abstract: 1400 infants develop Cerebral Palsy (CP) each year in England and Wales and 1/400 in the population suffer from the condition. So far the main treatment has been to prevent or limit the contractures and limb deformities that can occur. Premature delivery and asphyxia during birth are important causes of CP. Until recently it was thought that brain damage was immediate, but at least for birth asphyxia, it is possible to treat a baby after oxygen deprivation and successfully reduce injury. This is achieved by reducing the baby's body temperature, which increases the chance of normal survival by 50%.However, this is not always successful and it is now important to look furtherat the mechanism of damage and design improved treatments. The cellular suicide programme is turned on by oxygen deprivation or inflammation. However these different mechanisms seem to come together in a final common pathway, inwhich mitochondria (the power stations of the cell) are made to leak killer proteins, resulting in cell death. Our preliminary experiments suggest we can prevent it with drugs, and reduce brain damage in these unfortunate infants and reduce the unacceptably high incidence of CP in our society.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS
Title: The role of two key intracellular trafficking genes, VPS33B and VIPAR in development and disease.
Funder: Wellcome Trust

Abstract: Arthrogryposis, renal dysfunction and cholestasis syndrome (ARC) is a severe childhood disorder that affects many organs such as kidneys, liver, nerves and bones. We have previously found that defects in either of the two genes VPS33B or VIPAR can cause ARC. We also showed that deficiencies in these two proteins result in abnormal connections between the adjacent cells, which means that the cells start to grow abnormally. Similar type of abnormal cell growth can be seen in some of the common hum an diseases such as cancer and therefore further investigation of the underlying abnormalities in ARC would be useful not only in the context of ARC but will also inform on various changes in the cells that could be important in organ development and diseases like cancer. To study the cellular changes in ARC, the cells deficient in VPS33B or VIPAR will be used. Special types of microscopy and genechips will be used to investigate the processes affected by ARC. We will also set up methods to lo ok for treatments in ARC using the cell lines mentioned above. We will produce mice that mimic ARC syndrome clinical features and will allow testing of potential treatments prior to their use on patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: The molecular basis of cytochrome c oxidase deficiency.
Funder: Wellcome Trust

Abstract: Cytochrome c oxidase (COX) is an enzyme required for mitochondrial energy production, and consists of thirteen subunits. COX deficiency may be due to defects in genes coding for these subunits, or in genes coding for factors responsible for assembling COX correctly. Not all genes needed for COX assembly have been discovered. Mitochondrial disease affects 1 in 5000 children. COX deficiency accounts for 25% of cases and has severe and varied clinical features, affecting multiple organs. The prec ise diagnosis is difficult, and there is no effective treatment. We will investigate 45 children with COX deficiency where the genetic diagnosis is unknown. Conventional methods for discovering new genes are time-consuming and laborious. We will employ novel, rapid techniques known collectively as 'next generation sequencing'. We will also investigate the effect of various drugs on human cell cultures with COX deficiency. Our study will discover new gene defects, improve diagnosis and enab le testing in early pregnancy for affected families. We will provide insights into treatment options through our studies on cell cultures. Our research will lead to improved understanding of genetic mitochondrial disease and common diseases such as cancer, Parkinson's disease and organ failure after severe infection, where mitochondrial dysfunction has been demonstrated.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Genetic manipulation of MeCP2 in the human neuronal LUHMES cell line with a view to gene therapy of Rett Syndrome
Funder: Wellcome Trust

Abstract: Rett syndrome (RTT) is an autism spectrum disorder that is caused by mutationsin the gene encoding MeCP2, a chromatin-associated protein that binds mainly to methylated DNA and brings about gene expression changes. Being a single-gene disorder, whose symptoms are reversed by introducing MeCP2 into MeCP2-null mice, the use of gene therapy for this disease is possible. Recombinant adeno-associated viruses (rAAVs) are an extremely useful tool for gene therapy, demonstrating high transduction efficiencies, a lack of toxicityand the ability to reverse disease symptoms when used in clinical trials. Thisresearch aims to use rAAVs to target homologous donors into the nuclei of neuronal cells in vitro, to mutate the endogenous MeCP2 locus. To encourage homologous recombination to occur between the endogenous locus and the mutation-containing homologous donor; a CRISPR/Cas9 nuclease cassette will be used to nick the endogenous locus. This will produce mutant strains of neuronsthat can be phenotyped to gain insight into the cellular and molecular mechanisms involved in Rett syndrome. Using this rAAV/CRISPR/Cas9 technology


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Over two years for development of nanocomposite membrane covered stents for paediatric cardiac applications, an unmet clinical need.
Funder: Action Medical Research

Abstract: Background Congenital heart disease is one of the most common and important birth defects in children. Devices called stents are commonly used by surgeons in the treatment of conditions such as congenital heart disease. For example, a slender tube (stent) can be inserted into blood vessels to provide support like a scaffold. This helps to keep the vessel open improving blood flow. Stents can be made from different materials and coated stents have a thin surface covering. There are a number of limitations and complications in using these devices in children, such as rupturing of blood vessels during implantation, clot formation and a mismatch in the diameter of the implant and vessel after a few years due to growth of the child. The research project This team was approached by cardiologists that treat children with a request to develop a covered stent specifically tailored for children with congenital heart disease. Their aim is to replace the current PTFE-covered stents with a novel re-expandable covered stent. Current PTFE-covered stents have a high rate of blockage due to the materials and have low expandability, which results in clinical complications and repair procedures as the child grows. Complete coverage of a metal scaffold stent using a nanocomposite membrane developed by the team could circumvent these problems The material developed by these researchers has been shown to be non-toxic, to reduce the risk of blood clot formation and to be well-accepted by body tissues, not causing a rejection response. They have successfully demonstrated the use of nanocomposite materials in a world first artificial trachea, tear duct tube and bypass graft for legs. They have also worked on developing vascular stents for adults. This project aims to develop a new type of stent for children that could then be tested in clinical trials.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: CONGENITAL DISORDERS;CARDIOVASCULAR
Title: Right VENtricle function in CHildren – RVENCH study. A comparative study of the dysfunctional right ventricle in different congenital heart diseases
Funder: SPARKS

Abstract: One per cent of all live-born babies are affected by cardiac congenital malformations and intra-cardiac repair is associated with a low mortality (<5%). A growing number of such infants survive into adulthood with a high-pressure (hypertensive) right ventricle (RV). This can lead to RV dysfunction and heart failure. Management of this is expensive, each day on the PICU costs £2000 and each reoperation £25,000. A significant number are dying as a result, many years after cardiac surgery. Currently there is no targeted pharmacotherapy to improve RV function. This disease is associated with molecular and cellular changes in cardiac tissue and can be associated with changes in specific blood biomarkers. We plan to look at key signalling pathways, the Wnt and Cadherin pathways, in cardiac tissue and attempt to identify molecular biomarkers that can be used to determine the severity of the disease. We will study myocyte mechanics and contractility and the genes affected by such RV hypertension in infants undergoing cardiac surgery. The data will be correlated with clinical outcome parameters. This will allow us to design optimal intervention for each of the three identified pathologies both benefitting the patient and the healthcare economy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS;CARDIOVASCULAR
Title: Opportunity-Led Research Proposal: EUROCAT (European Surveillance of Congenital Anomalies)
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: This research award has funded one post-doctoral fellow (Nichola McCullough) for three years to work with the EUROCAT Joint Action (JA), and in particular extend its activities to Northern Ireland. EUROCAT is a network of population-based registries for the epidemiologic surveillance of congenital anomalies in Europe, covering approximately 30% of births in the EU. The co-ordinating centre for EUROCAT, with the European database, is at the University of Ulster, with its main funding from European Commission DGSanco. In line EUROCAT Joint Action (JA) 2010-2013 objectives, Nichola assisted with Annual Statistical Monitoring to detect, investigate and report on clusters of congenital anomalies and on trends in prevalence of congenital anomalies over time. Nichola conducted a survey of sources of data and prevalence of congenital anomalies in Northern Ireland, and current policies with regard to primary prevention. A seminar was then held to discuss the need for establishment of a register of congenital anomalies in NI, with the participation of many stakeholders. Nichola worked on a successful funding application to Chest, Heart and Stroke for the NI Baby Hearts Study, a study of risk and protective factors for congenital heart disease (CHD). This study, with Nichola as project manager, will continue to end 2016. The study will inform the prevention of CHD in NI and worldwide. Through liaising with the Northern Ireland Rare Disease Partnership and DHSSPSNI Nichola has contributed to the development of a framework for the Northern Ireland Implementation Plan for Rare Disease.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CONGENITAL DISORDERS;CARDIOVASCULAR
Title: Cardiovascular risk in early onset hypogonadism.
Funder: Chief Scientist Office, Scotland

Abstract: Over 1 in 300 children are born with atypical genitalia, which is commonly manifested as hypospadias, a condition where the opening for passing urine is not at the tip of the penis. Usually, these boys undergo surgery and are followed up for only a short period because of concerns about complications of surgery. Recent studies performed by myself have shown that boys born with hypospadias are at increased risk of high blood pressure and poor heart and blood vessel (vascular) health as they grow up. It is not clear, however, if this phenomenon is specific to hypospadias or if it would be found in other similar conditions too, or why this happens. To be able to improve clinical care and long-term health for such children, it is essential to: 1) investigate the cause of this vascular dysfunction; 2) identify those at greatest risk of this dysfunction; 3) understand how it develops over time; and 4) investigate whether it increases the risk of any complications following surgery. The proposed studies will help to answer these questions by comparing blood pressure data from boys with hypospadias from across the world and by undertaking studies on blood, urine and cell samples to look at the reasons why these boys might be at increased risk, and whether it is because of a mix of genetic and environmental factors. Blood vessels and skin samples from boys with hypospadias will be examined to see if wound healing is affected. Other boys who have had low testosterone throughout their childhood will also be invited for assessment of their blood vessel health, to see if boys with other conditions are also at risk of early cardiovascular disease. Overall, these studies will allow us to improve the care we currently offer to these people across their life-span


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CONGENITAL DISORDERS;CARDIOVASCULAR
Title: Targeting Usher syndrome with CRISPR mediated base editing
Funder: Medical Research Council

Abstract: Usher syndrome is a hereditary deaf-blindness syndrome inherited in an autosomal recessive manner. Gene replacement therapy has already had great success in the treatment of recessive loss of function mutations. However, replacement therapy is not an option for disease causing mutations exceeding the 4.7kb packaging capacity of the AAV virus or dominant gain-of-function mutations. A highly targeted form of CRISPR technology is base editing, which has the capability to target and reverse specific point mutations, such as G>A or C>T. My project focuses on adenine base editing (converting A to G), being mindful of minimising off target effects. First I will phenotype a new Ush2a W3947X mouse that has been generated through the GEMM programme at MRC Harwell. The mouse has an artificially induced A to G mutation that creates a premature stop codon and is predicted to have a retinal degeneration similar to a null mutation. I will initially design a base editing system using an adenine base editor (ABE) and test its efficacy in vitro using plasmid based assays. I will also test DNA base editing on blood cells harvested from USH2A patients who have the equivalent homozygous 11864G>A mutations. The transfected cells will be harvested, the DNA sent for sanger sequencing and the % correction determined. Currently, dcas9 tethered to the ABE is too large to fit inside the AAV virus and intein splicing will be used to deliver the Cas9-ABE construct in two halves. Experiments on the Ush2a W3947X mice can then be performed to investigate whether any physiological rescue has occurred: for example, comparing the outer photoreceptor layer width and electrophysiological response obtained from the treated mice to the control mice. If the project is successful, I would hope to help progress my findings into human clinical trials


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CONGENITAL DISORDERS;EYE
Title: Genetic models of human disease
Funder: Medical Research Council

Abstract: The aim of this programme is to use mouse genetics and genomics to explore gene function, as it relates to human development, physiology and disease and to identify mouse models of human disease. We have previously discovered more than 25 new mutations that affect eye development and function, and, with the aid of the mouse genome sequence, have identified the affected gene in almost all of them. Most of the mutations result in lethality when homozygous and identify genes that are important in a range of biological processes. In addition, we have used deletions to reveal recessive mutations that localise to particular genomic locations. We will continue characterisation of several of these mutant genes, two of which have known human disease homologues; Pax2, causing eye and kidney defects and Lmx1b causing nail-patella syndrome, and including glaucoma. This latter gene is subject to a collaboration with Simon John in the Jackson Labs, USA. A third mutant, for which we are still to confirm the affected gene, results in the congenital diagphragmatic hernia, a common human birth defect. One of the mutations revealed in the deletion analysis results in hair loss, and is a mutation in a palmityl transferase protein, which results in loss of a palmitoylation activity. Palmitoylation is a dynamic process which regulates the association of a protein with the cell membrane. The key substrate of this enzyme is unknown, although we have some affected candidates. This is the subject of a collaborative project with Ian Smyth at Monash. We have carried out a screen for novel recessive embryonic mutations, and identified a number of interesting genes which interact with the hedgehog signalling pathway. We have extended our collaboration with MRC Mammalian Genetics Unit, Harwell to screen for recessive mutations that affect vision and eye development. We have at least 5 new confirmed recessive mutations affecting eye morphogenesis, and have identified the affected gene in three of them. We are partners in the Eumodic programme, in which several hundred "knockout" mouse lines will be generated and comprehensively screened for defects in many systems of clinical importance. We will take any lines which demonstrate vision or other eye problems and extend the analysis to a more detailed histological level.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS;EYE;GENERIC HEALTH RELEVANCE
Title: MRC Wellcome Trust Human Developmental Biology Resource (HDBR)
Funder: Medical Research Council

Abstract: The Human Developmental Biology Resource (HDBR; www.hdbr.org) is unique, being the only tissue-bank that provides the international scientific community with access to: -High-quality materials from human embryonic and early fetal stages, including tissues for cell culture, RNAs from sub-organ specific regions and slides for spatial gene expression studies; -An in-house gene expression service (IHGES) that undertakes studies for registered researchers; -A unique web-based database for dissemination of human gene expression data spatially mapped to 3D models. To develop HDBR activities, and extend them to meet new challenges and opportunities, our key objectives are: -increase sample collection with a focus on intact specimens; -expand the range of IHGES studies, to include studies of noncoding RNAs and alternative spliced products, and to develop techniques to maximize expression information obtained from rare human tissues; -expand the range of materials provided, e.g. RNA, DNA and protein, from specific tissues to support sequencing, transcriptomics and proteomics projects; -interact strategically with large-scale initiatives focusing on human development and disease. By also improving our engagement with current and potential users, we will adapt the HDBR to meet the needs of functional gene characterisation, for the new genetics technologies.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CONGENITAL DISORDERS;GENERIC HEALTH RELEVANCE