Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Within the nucleus, DNA is packaged with proteins into chromatin. Some parts of the genome are activated in order to produce the proteins and RNAs necessary to make and maintain different types of cells. However up to 50% of the DNA in animal genomes is comprised of repetitive DNA derived from transposable elements or invading viruses, and these regions are kept inactive by packaging them into a type of chromatin called constitutive heterochromatin. Some genes are also kept silent by constitutive heterochromatin. Given that constitutive heterochromatin occupies a substantial fraction of animal genomes, it is not surprising that its disruption affects many nuclear processes in addition to the repression of repetitive elements. Constitutive heterochromatin has both regulatory and structural roles in the nucleus, and dysfunction is associated with human disease including cancer. In addition, heterochromatin impedes the reprogramming that is necessary for the production of induced pluripotent stem (iPS) cells, which hold promise for regenerative medicine. Therefore advancing knowledge of constitutive heterochromatin is important for understanding genome regulation and disease. New knowledge has potential to identify new therapeutic targets and improve the generation of iPS cells. Despite the importance of constitutive heterochromatin in diverse areas of biology and disease, our understanding of its formation and function is extremely limited. Heterochromatin components are similar across animals, and work in model organisms has been instrumental for our current understanding of its formation and function. There is a strong history of advances made in model organisms having translational consequences in medicine, highlighting the importance of their use in basic research. Our programme will use the C. elegans model, which provides a simple but powerful system for discerning conserved mechanisms of heterochromatin formation and regulation in animals. Our programme has three distinct but interrelated aims. The first aim is to further understanding of how constitutive heterochromatin forms. We will visualise when and where heterochromatin forms in the nucleus using new super-resolution microscopy methods and by mapping the locations that heterochromatin proteins are found on DNA. We will determine the roles of heterochromatin proteins by studying strains in which they are defective and assessing the consequences of their loss. We will also investigate whether we can cause heterochromatin to form by artificially bringing different proteins to DNA. In our second aim, we will use a parallel genetic screening technique to identify a large-scale network that contains heterochromatin components, heterochromatin regulators, and proteins that are involved in causing defects when heterochromatin is not functional. We will study the functions of new genes in C. elegans and collaborate with other investigators to study shared important proteins in humans. In the third aim we will investigate the nature of the interactions between heterochomatin loss and disease pathways to help understand the abnormalities caused by heterochromatin dysfunction. We will also study whether loss of heterochromatin makes cells more receptive to abnormal signals such as those for cell division, which could increase risk of cancer or other diseases. Our programme will further our understanding of how constitutive heterochromatin forms, identify new components of heterochromatin, and determine how heterochromatin dysfunction causes pathologies. Because of the conservation of genes and biological principles across different animals, our findings might identify new biomarkers of human disease and/or therapeutic targets.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Vascular smooth muscle cells (VSMCs) are major components of blood vessel walls, where they regulate blood flow and blood pressure. In response to inflammation and injury in the blood vessels, VSMCs can change into a so-called 'synthetic' state, whereby they become migratory, proliferate and take part in tissue repair. This unusual plasticity of VSMCs is vital for the maintenance of healthy vasculature throughout the lifespan. Individual VSMCs appear to differ in their capacity to switch to a synthetic phenotype and show heterogeneity in the levels of contractile VSMC markers. Intriguingly, these cells also originate from two different embryonic tissues, and origin-specific differences in their 'eagerness' to undergo phenotypic switching in response to injury have been observed. We therefore hypothesise that individual VSMCs are differentially 'primed' for this response depending on both their embryonic origin and yet unknown factors, and that their differential plasticity is reflected by their global gene expression profiles. The project aims to further elucidate the mechanisms underlying VSMC plasticity. It will first take advantage of the state-of-the-art method of single-cell RNA sequencing (scRNAseq) to profile gene expression genome-wide in multitudes of individual VSMCs. A comprehensive bioinformatics interrogation of the scRNAseq data will then be carried out to formulate hypotheses on the potential genes and gene networks that underlie VSMC plasticity. Finally, these hypotheses will be tested experimentally in vitro and in vivo. Bioinformatics data analysis is integral to the project, but the balance between the experimental and computational work can be adjusted to suit the candidate's objectives.

Improving the yield of crops will be necessary if the rising global crop demand is to be met. The majority of research to improve wheat yield has focused on improving the crop's photosynthetic efficiency. In this project, improving wheat yield will be investigated from a different perspective: regulation of growth and the allocation of the products of photosynthesis to growth versus storage. During the day, plants photosynthesise. The products of photosynthesis are partitioned between sucrose, which is either kept in the leaf or exported to other parts of the plant to be used for instant growth, or starch. At night, starch is degraded to allow growth in the absence of light. It is understood that starch degradation in Arabidopsis occurs linearly and is at least in part under circadian control. This is because the rate of starch degradation adapts to the length of the night to ensure that the starch reserves are not depleted before dawn. Correct utilisation of starch reserves has been linked to optimal growth at night making this area of research important to improving yield. In this project, a variety of approaches will be used to transfer knowledge gained in Arabidopsis to wheat. Genetic approaches will allow the determination of genetic linkage to allocation traits while biochemical techniques will be used to investigate the diel changes in starch and sugars. This project seeks to investigate improving the yield of an important crop plant from a novel perspective.