NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating barriers and facilitators for Health Care professionals in utilising mindfulness interventions to improve psychosocial difficulties in eating behaviours for people with Cystic Fibrosis
Funder: The British Academy

Abstract: Cystic Fibrosis (CF) is a life-limiting, progressive autosomal recessive inherited disorder caused by defects in a recessive gene, the cystic fibrosis transmembrane conductance regulator (CFTR) increasing the production of thick, sticky mucus and impairs the functioning of the respiratory tract and impacts on digestive system organs leading to the maldigestion and malabsorption of nutrients. Symptoms impact strongly on eating behaviours and nutritional and weight status which is closely linked to respiratory status. There is little research on eating experiences and behaviours, recent research has explored mindful eating practices to gain a fuller understanding of eating behaviours and to develop bespoke interventions adapted to the experiences of people with CF (PwCF) which support psychological wellbeing alongside improved eating behaviours. Research demonstrates a lack of healthcare professional (HCP) knowledge and experience in mindful eating. The present study aims to investigate the experiences of HCPs using bespoke mindful eating interventions for PwCF.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: CONGENITAL DISORDERS
Title: Transcriptional Control of Vertebrate Limb Development
Funder: Medical Research Council

Abstract: Limb defects are the second most common congenital abnormality present in human live births and diseases affecting the musculoskeletal system are a significant clinical problem, particularly in the older population. The goal of our work is to understand how the limbs form normally during embryogenesis and the genesis of limb abnormalities and diseases that affect the musculoskeletal system in humans. ||Limbs are formed from specific regions of the flank of the embryo. At early stages of embryonic development, the forelimb and hindlimb buds are morphologically uniform and indistinguishable from one another. During subsequent steps of development however, dramatic changes take place. Each bud develops to form a network of interconnected limb elements e.g. bones, muscles, and tendons-with morphologies characteristic of either the forelimb or hindlimb. We are using vertebrate animal models to understand the mechanisms that control the initiation of limb bud formation and the subsequent construction of the individual limb elements during embryonic development. A longer-term aim is to apply these findings to develop to potential therapeutic approaches that could contribute to maintenance and possible regeneration of these structures in later life.||We use the developing limb as a model system using predominantly mouse and chick model organisms but also zebrafish and frog (and in future, as part of collaboration, we also plan to include Bat). In general our strategy is to interrogate gene function using a combination of coordinated gene misexpression and gene deletion experiments, often in more than one model system. In the mouse, we take advantage of gene conditional alleles and a repertoire of Cre deleter transgenics that we have developed ourselves or have collected. We often include transgene reporters to aid in phenotyping. In the chick, we are using genetic techniques to misexpress genes (either retroviral vectors or electroporation or direct application of recombinant proteins or substances) in combination with more classical embryological approaches. A new and important aspect of current and future work is to develop the use of in vitro techniques as an alternative, complementary approach to our in vivo models. Currently this involves the generation and characterisation of cell lines derived from transgenic reporter mouse lines we have produced and collected.|


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CONGENITAL DISORDERS
Title: Identifying factors required for genomic DNA methylation using the imprinting control protein ZFP57
Funder: Medical Research Council

Abstract: Mutation of ZFP57 in humans causes a "complex imprinting disorder" (CID), i.e. one impacting several loci across the genome. Patients have distinctive hypomethylation at specific genes, and clinical features including congenital anomalies and developmental delay. These data suggest that ZFP57 is required for normal imprinting. We will exploit ZFP57 to identify the DNA motifs it recognises, the imprinted genes it controls, and proteins it associates with. (A) We have developed N- and C-terminal HaloTag constructs with ZFP57 (hZFP57). DNA bound to hZFP57 will be affinity-purified and high-throughput sequenced. We will bioinformatically map the motifs bound by ZFP57, then use EMSA and reporter assays to assess role of putative motifs in control of gene expression. We will analyse DNA from a patient cohort with clinical/ molecular features of imprinting disorders, to seek mutation in these motifs as a cause of disease. (B) We will perform genomewide methylome analysis of patients with CIDs, by affinity-purifying methylated DNA with MethylCollector, and sequencing on Illumina GA2, comparing patients and controls to highlight CpG islands hypomethylated in patients. SNP analysis of gDNA and cDNA will be used to verify novel imprinted genes. Targeted methylation analysis of candidate imprinted genes will be developed to assess the role of these genes in imprinting disorders. (C) To identify protein partners of ZFP57 we will use two strategies: (i) hZFP57 affinity to enrich protein cofactors, which will be analysed by mass spectrometry and N-terminal sequencing. (ii) exome-sequencing of patients with CIDs but not ZFP57 mutations. Protein candidates will be stratified by literature survey and expression data, and then validated by molecular testing in vitro, and genetic analysis in patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Ciliopathy disease gene identification by whole exome medical resequencing
Funder: Medical Research Council

Abstract: We have ascertained and sampled DNA from about 250 individuals with a broad range of known or suspected ciliopathy phenotypes, but with a common theme of left-right laterality defects. These patients are confirmed to be mutation negative for known genes, or have been excluded from linkage to known loci in multiplex or consanguineous families. About 50% of disease genes for Meckel-Gruber syndrome and primary ciliary dyskinesia still remain to be identified, and many families with inherited forms of left-right laterality defects have an unknown genetic aetiology. We estimate that this research will identify a minimum of 10-12 new genes, comprising the majority of the remaining genes in this group of conditions. To discover new ciliopathy genes, we will perform whole exome sequencing for 100 individuals, including trios with an orphan ciliopathy. We will use our own successful bioinformatics workflow to distinguish putative pathogenic mutations from benign polymorphisms, even in the context of genetic heterogeneity. We will prioritize potential pathogenic variants in functional candidate genes on the basis of putative function, and our own data from a reverse genetics screen for ciliogenesis. Collaboration with other groups will allow us identify further mutations in a new gene for cohorts of patients with a ciliopathy and/or a retinal degeneration. This will also delineate an allelic series for a new gene, and may define genotype-phenotype correlations. We will collaborate with external groups to assess zebrafish embryo morphant phenotypes for 2 or 3 newly-identified ciliopathy disease genes. In some instances (for example if we need to prove the pathogenicity of a missense mutation), we will perform straight-forward functional characterization of the protein. This will include sub-cellular localization using confocal immunofluorescence microscopy and the effect of RNAi or a missense mutation on ciliogenesis or protein localization.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Molecular and cellular characterisation of an important new human DNA repair disorder
Funder: Medical Research Council

Abstract: We have recently identified a novel inherited syndrome in the Ohio Amish community. Affected individuals have features which overlap with known DNA repair disorders including Cockayne's syndrome (CS), ataxia telangiectasia (AT) and xeroderma pigmentosum (XP). The eldest affected individuals also show signs suggestive of premalignant changes in their skin. Because the features of this syndrome overlap with those of multiple DNA repair disorders, we hypothesize that the underlying molecular defect probably affects more than one DNA repair process. We have identified the causative mutation in the Amish community and find it to be a missense alteration in an essential gene. We have access to unique patient material (comprising fibroblast and lymphoblastoid cell lines from affected individuals and unaffected family members) and plan to use these and other established resources to develop a clearer understanding of the role of this protein in DNA damage responses and other cellular pathways, with the aim of understanding how the molecular defect results in the cellular phenotypes and eventually the symptoms of the affected individuals. To do this we will use cell-based functional assays, and molecular biology approaches to investigate protein interactions. We have already developed a substantial body of unpublished work and technical resources for this project and so are perfectly positioned to make rapid and effective progress. Successful completion of the project will have implications for our understanding of cellular pathways that regulate genome stability. This is vital as the correct operation of these processes is crucial to limit mutagenesis and prevent tumorigenesis and neurodegeneration in normal individuals. Our findings will also have direct patient benefit because they will provide a better understanding of the nature this condition, facilitating the clinical management of affected individuals.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Characterisation of the Z-pocket for the treatment of alpha-1-antitrypsin deficiency
Funder: Medical Research Council

Abstract: The most common cause of alpha-1-antitrypsin (a1AT) deficiency is the Z-mutation (E342K), found in 1 in 25 people of European descent. Emphysema and chronic obstructive pulmonary disease (COPD) result from the impaired secretion of a1AT, and liver manifestations, such as cirrhosis, fibrosis and cancer, are caused by the accumulation of misfolded 'polymers' of a1AT in hepatocytes. Development of lung and liver disease requires two affected alleles, the most common being ZZ and ZS. The prevalence of ZZ and ZS is 1:2000 across Europe, but differ in distribution (ZZ is 1:500 in Latvia and ZS is up to 1:200 in Spain and Portugal). The underlying protein, a1AT, is a member of the serpin family of protease inhibitors. Its main role is to protect tissues from proteases released from inflammatory cells, including neutrophil elastase. ZZ homozygocity results in circulating levels of 15% normal, and a mere doubling of secretion would be sufficient to protect from development of disease. Currently there is no effective treatment for a1AT deficiency. As part of a previous MRC project grant, we determined the molecular basis of a1AT polymerisation, and unexpectedly discovered how the Z-mutation may affect protein folding. The Glu-to-Lys mutation alters the conformation of an adjacent loop, extracts a Phe from a buried position, and creates a 350 cubic angstrom pocket. This pocket exists in the native protein in solution and can be filled by hydrophobic compounds. A compound similar to Phe (4-phenylbuteric acid) has been shown to be effective in cell and animal models as a chemical chaperone for the improvement in secretion of Z-a1AT. The goal of the current grant is to establish the existence of this 'Z-pocket' in solution, to determine the mode of action of PBA, and to establish tools that will allow the identification and characterisation of novel chemical chaperones for treatment and prevention of a1AT-deficiency caused by the common Z-mutation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Chemical reversion of nuclear shape and other defects of Hutchinson Gilford Progeria Syndrome and Lamin A/C depleted cells
Funder: Medical Research Council

Abstract: One of the features shared by laminopathies is the disorganization of chromatin structure and misshapen nuclei. Hence, one of the main challenges is to identify new therapeutic strategies to reverse the nuclear shape defects in progeric and dystrophic cells to improve the patient's lifespan. This project investigates the mechanisms by which a new small molecule that we have called Remodelin rescues the nuclear morphology in progeric and dystrophic cells as well as in normal ageing cells. By modifying Remodelin to make it suitable for use with "click-chemistry", we have identified its cellular target responsible for the nuclear shape rescue. We will use a combination of in vitro assays, such as Biacore-based studies, to understand how the binding of Remodelin modulates the function of its target. We will then study in depth the mechanism by which Remodelin's impact on the target protein to rescue nuclear architecture. Next, by using cells derived from Hutchinson Gilford Progeria Syndrome (HGPS) patients, as well as normal ageing cells and Lamin A/C depleted cells, we will assess the effects of Remodelin treatment on nuclear architecture related functions, such as chromatin organization, cellular proliferation and DNA repair as well as cell motility and invasiveness potential. This will tell us whether Remodelin improves global cellular fitness in these different models. Finally, after defining these parameters in cellular systems, we will carry out in vivo assays with sophisticated mouse models comprising premature ageing HGPS mice as well as a Lamin A/C knock out mouse model of muscular dystrophy. These will be treated with Remodelin and its derivatives to see whether we can improve their phenotypes such as muscular and heart functions, bone density and weight as well as their global lifespan. Our work will thus shed light on a very challenging area of research - nuclear architecture associated diseases, which is likely in the longer term to influence public health.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS
Title: A randomized, double-blind, parallel group, placebo-controlled trial of metformin in tuberous sclerosis complex.
Funder: Department of Health (England)

Abstract: Background Tuberous sclerosis (TSC) is a genetic disorder characterised by the development of benign tumours (hamartomas) secondary to loss of regulation of the mTOR intracellular growth pathway. Problems include epilepsy, learning and behavioural difficulties, disfiguring facial hamartomas, haemorrhage from kidney tumours and hydrocephalus from intraventricular astrocytomas (SEGAs). The drug rapamycin inhibits mTOR and temporarily reverses tumour growth in TS clinical trials, but its use is likely to be limited by severe side-effects. Metformin is widely and safely used in type-2 diabetes. It inhibits mTOR via AMP kinase and inhibits tumour cells in vitro and in mice, and reduces risk of tumour development in vivo.(1-4) Therefore metformin may be a safe and effective treatment for TSC. Aims The primary aim is to investigate the effects of metformin on renal tumour size in TSC patients. The secondary aims are to investigate the effects of metformin on: -SEGAs (brain tumours) -Facial angiofibromatosis (facial tumours) -Quality of life -Cognitive abilities -Epilepsy -And to assess the side effects of metformin in TSC patients. Plan of Investigation This is a randomized double-blind parallel group placebo-controlled trial. 100 participants will be recruited from FOC’s TSC clinic (1 of 6 specialist UK TSC clinics). Participants will be randomized 1:1 to metformin and placebo groups. Baseline assessments will include assessment of renal and brain tumour volume, facial tumour distribution, cognitive ability, quality of life, and epilepsy. Therapy with metformin/placebo will run for 12 months. At 6, 12 and 18 months facial tumour distribution and epilepsy will be reassessed. At 12 months cognitive ability, quality of life and brain and renal MRI tumour volume will be reassessed. At 6 and 18 months a renal ultrasound scan will be performed. Kidney and liver function and blood glucose will be monitored throughought. Potential Impact About 5000 people in the UK have TSC. Almost all have disfiguring facial tumours and kidney tumours that can cause pain and death. Many have epilepsy (75%) and learning and behavioural problems (50%). There is no disease modifying treatment; standard care is limited to symptom management and intervention when necessary. If metformin reduces tumour size or rate of growth then a reduction in pain, disfigurement, risk of death, and amount of clinical care required is expected. If it also reduces cognitive, behavioural, and epilepsy severity then demand for learning and social support and anti-epileptic drugs will also reduce. Metformin costs about £12 per year. If its use reduces the above burdens then this will be more effective and considerably cheaper than standard care.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS
Title: Reducing inflammation in cystic fibrosis lung disease by targeting expression of CFTR in the endothelium with a copper-tobramycin complex
Funder: The Dunhill Medical Trust

Abstract: The cystic fibrosis transmembrane conductance regulator protein (CFTR) is a chloride ion channel expressed in all epithelial cells that is defective in cystic fibrosis (CF), causing lethal infectious inflammatory lung disease. We propose that i) defective CFTR in endothelial cells contributes to excessive inflammation in bronchial tissue in CF, and ii) tobramycin, used to treat infection, has direct anti-inflammatory effects on the endothelium. Tobramycin binds copper, and we have found that the copper-tobramycin complex has anti-oxidant activity and increases expression and membrane distribution of CFTR in lung microvascular endothelial cells in vitro. We will use cell culture, gene silencing techniques, models of inflammation and patch clamping to investigate the proposed role of endothelial CFTR in inflammation, and the effect of tobramycin and copper-tobramycin on CFTR function. Urine samples from patients receiving tobramycin will be analysed by HPLC to test for the presence of copper-tobramycin


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: A genetic dissection of brain and heart phenotypes in the Tc1 transchromosomic mouse model of Down syndrome.
Funder: Wellcome Trust

Abstract: Down syndrome (DS) is the most common known form of mental retardation and people with DS have many other susceptibilities to disorders, such as heart disease and dementia. Such disorders occur with a higher frequency in DS humans than in the rest of the population. DS is known to occur as a result of having three copies of chromosome 21, rather than the normal two. Therefore the individual disorders that arise in DS must happen because of the wrong gene 'dosage', but working out which genes are responsible for which individual disorders, such as heart malformation, or learning deficits, has proven very difficult. Now new technologies, in which we have expertise, mean we can cut chromosome 21 into pieces and then look in a mouse model to correlate the presence of each piece with that of an individual disorder. In this way we can determine which region of the chromosome carries genes important for, for example, heart disease. We are able to do this because we have created a unique mouse model that carries human chromosome 21 and that, as we have already shown, is a good model for DS. We will collaborate with three specialist laboratories so that we have a well-defined and robust assay for brain and heart function in our DS mouse model, and from this we can get to the underlying dosage-sensitive genes. This is important for understanding what goes wrong in DS, and for designing future therapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: A novel approach for the analysis of de novo point mutations in the human FGFR3 gene.
Funder: Wellcome Trust

Abstract: One ultimate and very challenging goal in human molecular genetics is to find out how DNA changes arise and what consequences they have for an individual and offspring. Point mutations involve just a single letter of the DNA code and are among the rarest changes in our DNA. Yet they are a major source of genetic variation between individuals, and a substrate for evolution with the potential to cause heritable diseases and cancers. In this work, we will isolate and study particular known mutating sites within the human fibroblastgrowth factor receptor 3 gene by modifying a powerful new technique we have recently developed. This gene has a crucial role in bone development, is involved in certain non-aggressive cancers, and most interestingly, harbors the most mutable site in the human genome known to date causing the inherited disease achondroplasia. Moreover, there are nine nearby mutation sites that had been identified in other congenital diseases and particular types of cancer. By ex tensive investigation of newly arising mutations at these sites we will provide novel quantitative and molecular information on the mutation processes operating inside this gene. Our new approach is generic and should be applicable in principle to any mutation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS
Title: Selfish mutations in the testis: impact on evolution and disease.
Funder: Wellcome Trust

Abstract: All disease related to genetic alterations starts by the process termed mutation, whereby a copying error arises in the DNA. When this occurs in the eggs or sperm, it can be transmitted to the next generation. We previously identified a process in the germ cells of men's testes that promotes harmful mutations, so that they paradoxically increase in the sperm. This is because the mutations give a growth advantage to the cells in which they occur, which is why we term them selfish . So far this mechanism has been demonstrated only in rare conditions with severe growth disturbance, malformation, or death in the newborn child. However these may represent the most obvious, extreme cases, with the underlying process being more common than we currently realise, and also contributing to cancers and other common diseases. This proposal aims to harness new DNA sequencing technologies with various computational approaches to explore the consequences of selfish mutations. Hence we plan t o measure the levels of additional relevant mutations in sperm; to determine whether human DNA shows signs of these mutations as past events; to identify the mutations directly in testes; and to develop ways to find these mutations in the entire human genome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CONGENITAL DISORDERS