NIHRDataInsights/HRCSData huggingface dataset:
Title: Towards Dolly: Edinburgh, Roslin and the birth of modern genetics
Funder: Wellcome Trust

Abstract: This project will catalogue, preserve and conserve five internationally-important collections which tell the story of how Edinburgh became one of the world's centres of genetics research. These collections are (1) the library, papers and photographic slides of the Roslin Institute (2) papers of J. C. Ewart (3) papers of C. H. Waddington (4) records of the Institute of Animal Genetics (5) F.A.E. Crew Collection. We will open up these collections and set them in their context, in terms of the history of scientific research and of the human story behind the work in Edinburgh which they reveal. The bulk of the material is archival or printed, produced between 1890 and 2007, but there are older items dating back to 1573. These earlier items indicate the deep roots of the Edinburgh genetics community; they also present us with a challenging range of material needing different levels of work. These collections require preservation work to prevent serious deterioration, and are largely uncatalogued or accessible only via basic handlists. An experienced Project Archivist and Book Cataloguer will create appropriate online catalogue records, with generous interpretative support from academic colleagues. The Archivist and Cataloguer will perform basic remedial preservation work, mainly cleaning and rehousing items; an accredited Conservator will repair items whose current physical condition prevents usage. This material will become accessible to a world-wide audience and prepared for eventual digitisation. We will also scope other collections still in private / departmental care for future projects.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Identification of the regulator of chromosome architecture: investigating a novel activity promoting mitotic chromosome condensation
Funder: Wellcome Trust

Abstract: Vagnarelli et al identified a novel, condensin-independent mechanism of chromosome compaction which they called the Regulator of Chromosome Architecture (RCA). The nature of the RCA is still unknown. The aim of my project is to identify the RCA and the mechanism by which it promotes chromosome condensation, to investigate the relative contributions ofthe RCA and the condensin-dependent pathway to the establishment and maintenance of mitotic chromosome architecture and to measure the change in the mechanical properties of chromatin upon entry into mitosis. I will use in vitro chromatin reconstitution to define the non-condensin components of purified mitotic cell extract responsible for chromatin compaction. The chromatin compaction state will be assayed by a variety of techniques including Atomic Force Microscopy. Based on preliminary results, the initial focus will be on the role of mitotic histone post-translational modifications (PTMs), a comprehensive survey of which will be compiled by SILAC-based mass-spectrometry.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Deprotection of cohesion in meiosis II
Funder: Wellcome Trust

Abstract: The faithful segregation of chromosomes requires the cohesion of sister chromatids, a function mediated by the cohesin complex. In mitosis, cohesin iscleaved in one step along the length of the chromosomes to allow sister chromatid segregation. In meiosis, however, cohesin is cleaved in a step-wise manner. Cohesin at chromosome arms is cleaved in meiosis I to allow homologue segregation but protected around the centromeres until meiosis II, when its cleavage triggers sister chromatid segregation. How centromeric cohesin is "deprotected" to allow its cleavage during meiosis II is unknown. The overall aim of my project is to determine how pericentromeric cohesin becomes susceptible to cleavage in meiosis II. To do this, I will first identify post-translational modifications of cohesin in meiosis II and their role in allowing cohesin cleavage. Secondly, I will investigate how the cohesin protector Sgo1/PP2ARts1 is inactivated in meiosis II. I will determinethe behaviour of the protector throughout meiosis and investigate why it is lost from the pericentromere at the end of meiosis II. Furthermore, I will interactors and post-translattional modifications of Sgo1 and study how these affect its function. Overall, I will gain insight into the mechanisms governing the cohesin deprotection in meiosis II.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Protein phosphorylation in circadian clocks
Funder: Wellcome Trust

Abstract: Circadian clocks are endogenous pacemakers found in many organisms, generatingapproximately 24h rhythms. Since many cellular processes are clock regulated, understanding its mechanism is very valuable for scientific and economic purposes. The plant circadian clock has been studied in detail by transcriptomics, but recent studies at the protein level at least add unforeseen complexity and possibly challenge the basic clock principle. By a mass spectrometry based phosphoproteomics approach we aim to resolve the following two paradoxes of the Arabidopsis circadian clock: (1) evidence is increasing that rhythmicity of circadian regulated transcripts and corresponding proteins do not correlate well; (2) although the established view of the plant circadian clock is a transcriptional-translational feedback loop, an oscillator has recently been shown to exist which is independent of rhythmic gene expression. By detecting rhythmic phosphopeptides in wild-type and clock mutant plants we aim to resolve these paradoxes by testing the following two hypotheses: (1) it is the rhythm of phosphorylated protein


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulation of miRNA biogenesis involved in neuronal differentiation
Funder: Wellcome Trust

Abstract: Many cellular functions depend on tightly regulated expression of various proteins. Canonical control of the protein expression is associated with transcriptional regulation. However, only recently the small non-coding RNAs called microRNAs (miRNAs) were identified as post-transcriptional regulators of gene expression. In a typical manner miRNAs originate similarly to the coding RNAs and are processed in a multi-step maturation process. It has been shown that miRNAs are very important for proper functioning of all human tissues. Interestingly the human nervous system contains over 70% of all miRNAs. However, despite the important role of miRNAs, little is known about the mechanisms regulating their biogenesis. The current project is going to identify unknown factors involved in the regulation of selected miRNAs that have been shown to play important roles during neuronal development. RNA chromatography coupled with quantitative proteomics will be used to identify the putative regulators. These factors will be validated using RNA-immunopreciptiation followed by qRT-PCR assays and their functional


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Probing the structural rearrangements during 40S ribosomal subunit synthesis in yeast
Funder: Wellcome Trust

Abstract: Ribosome maturation involves hundreds of ribosome assembly factors (AFs) that regulate the time-wise association of ribosomal proteins. Although the RNA is the catalytically active component in ribosomes, the ribosomal proteins play crucial roles in rRNA folding and maintenance of long-range rRNA interactions.Intriguingly, preliminary structure probing data from the lab revealed that AFs required for the formation of the 40S head domain dramatically alter the interactions of ribosomal proteins with rRNA, several of which appeared misplaced in the 40S assembly intermediates. This misplacement presumably has a major impact on the overall structure of the rRNA. We hypothesize that AFs function by preventing certain ribosomal proteins from adopting their final conformation in 40S intermediates until final rRNA processing and folding steps have been completed. The proposed work aims to understand the mechanism and functional importance behind this initial misplacement by addressing (i) how this affects the global structure of the 18S rRNA, (ii) how this is linkedto 18S rRNA maturation and (iii) by dissecting the ribosomal protein-rRNA interactions required for the 18S rRNA maturation. The outcomes should provide substantial novel insights into the function of AFs in ribosome remodelling and rRNA folding.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Improving the ability of health systems to deliver essential, hospital services - Examining strategies targeting seriously ill children and newborns in Kenya.
Funder: Wellcome Trust

Abstract: My previous work established that a set of simple interventions can improve care for children in rural Kenyan hospitals. The close working relationship established with government and others has now resulted in basic components of the previous intervention being implemented routinely. To assess new strategies that could be used widely in rural hospitals and adapted to different areas of patient care that might further improve delivery of life-saving essential services I plan to examine a strateg y that links: i) performance feedback and ii) mentorship and peer to peer support for relevant clinical and nursing managers in rural hospitals. I will then use a variety of research methods over a period of up to 4 years to: 1. Comprehensively assess the services provided by these hospitals 2. Examine whether providing mentorship, peer to peer support and performance feedback improves care and how influences from different levels of the health system and hospital hierarchy shape attempts to improve care for seriously ill children and babies. 3. Examine over the course of the several years why some hospitals perform well and others badly to help design better strategies to improve hospital care in the future


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Single-molecule conformational dynamics of DNA polymerase I in live bacteria
Funder: Wellcome Trust

Abstract: DNA polymerase I (Pol I) is a prokaryotic polymerase involved in DNA repair. It consists of three domains polymerase, 3'-5' exonuclease and 5'-3' exonuclease, where the polymerase is further divided into thumb, palm and fingers subdomains. The fingers subdomainis highly flexible, and allows the protein to adopt open and closed conformations that are crucial for its mechanistic cycle. Although Pol I has been well studied in vitro, we have a poor understanding of its mechanism in vivo. In this project, we would like to probe the structure and dynamics of Pol I in vivo, by means of single-molecule Förster resonance energy transfer (FRET). Protein constructs will be doubly labelled with bright and stable organic fluorophores, and internalized into live E. coli using electroporation. We will employ total internal reflection fluorescence (TIRF) microscopy to visualize and track single molecules and measure FRET signals inreal time. This would allow us to see the effect of DNA damage on the localization and conformation of Pol I, and conformational changes in Pol I during DNA synthesis. The project would have a significant method-development component and would yield a general method for probing conformational dynamics of soluble proteins in live bacteria.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding the mechanism of cohesion establishment
Funder: Wellcome Trust

Abstract: The cohesin ring topologically entraps sister chromatids to ensure timely and error-free chromosome segregation during cell division. In interphase, cohesin is continually loaded onto and removed from the DNA by kollerin and releasin complexes, respectively. Acetylation of the ring is crucial for cohesion establishment this modification is believed to overpower the antiestablishment activity of releasin. In many systems outside of yeast, another essential protein sororin is also required for releasin neutralisation. One of the minor aims of this project is to conduct a small-scale screen to determine whether or not sororin exists in Saccharomyces cerevisiae. The primary goal of this project is to investigate the anti-establishment activity of releasin. One of the key aims is to determine whether releasin has the ability to physicallyremove cohesin from both DNA strands. The bulk of this project will involve reconstituting releasin activity in vitro by building on an existing physical assay for cohesion. Ultimately, this project aims to establish the minimal requirements for the anti-establishment activity of releasin.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural and functional study of Fibroblast Growth Factor Receptor family members
Funder: Wellcome Trust

Abstract: Fibroblast Growth Factor Receptors 1-4 (FGFRs) form a receptor tyrosine kinasesubfamily which play an essential role in the regulation of cell differentiation, growth, migration and survival. Previous studies report that single mutations located in the transmembrane domains (TMD) of FGFR3 and 4 lead to aberrant signalling via constitutive activation and cause various human pathologies such as skeletal disorders or cancer. Structural or functional data on the mode of action of these mutants remains fragmentary. The major aim of this project is to gain deeper structural insights into dimer formation and activation of both wildtype and aberrant receptors. Towards this overall aim, key goals of the project are: 1. Isolate full-length constructs of FGFRs 2. obtain a full-length structural model of wildtype and mutant FGFR3/4 by EM 2D class averages of negatively stained samples. 3. obtain crystal structures of FGFR4 ectodomain (and full length) 4. examine the cell surface dimerisation and kinase activity of mutant receptors 5. simulate the dynamics of wildtype and mutant TMD dimers in an lipid bilayerenvironment 6. simulate the dynamics of an FGFR model including individual extra- and intracellular domains 7. examine the interaction of FGFR with adaptor proteins.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular mechanisms of Repulsive Guidance Molecule (RGM) action
Funder: Wellcome Trust

Abstract: Repulsive Guidance molecules (RGMs), a family of membrane-anchored glycoproteins, are involved in two key signalling pathways: the Neogenin (NEO1) [1] and bone morphogenetic protein (BMP) [2] pathways. RGMs control and fine-tune a wide range of functions from neural development [3] to leukocyte migration [4], and are implicated in several severe diseases, for example juvenile hemochromatosis [5,6] and cancer [7]. The aim of this research project is to fully characterise the actions of RGMs at the membrane interface with both of these pathways. This will involve biophysical and cell-based measurements to build on a crystal structure of RGM bound to BMP (obtained in my first rotation project) to understand how RGMacts as an activator in this pathway. It will also involve crystallisation of complexes involving proteins from both pathways to study how the two pathways are connected. I will also work towards crystallising the full-length type I membrane protein BMP-receptors to gain insight into how the signal is transmitted across the membrane. This will be supported by functional studies using fluorescence techniques, biophysical and cellular analyses.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating differences between sense and antisense transcription and how these differences impact gene expression regulation
Funder: Wellcome Trust

Abstract: The non-coding transcriptome in eukaryotic cells is likely to play a major role in modulating patterns of gene expression though the direct effect of the transcripts and/orby the ability of the act of transcription to influence the epigenome and thus the phenotype displayed by cells. The non-coding transcriptome of the yeast Saccharomyces cerevisiae, specifically the non-coding antisense transcripts/transcription will be the focus of this project. S. cerevisiae offers many advantages for such a study, particularly its compact, well characterised genome and epigenome as well as no system to generate siRNAs which can complicate functional studies on the non coding transcriptome. This project aims to determine (i) how the transcription of antisense RNAs differs from that of sense RNAs at the level of post-translational modification to RNA polymerase II and the chromatin template (ii) how such differences might affect RNA stability and localisation. In addition, the role of RNA:DNA:DNA triplex formation as a mechanism through which some ncRNAs mediate their effect will be investigated.As a result of this project a better understanding of the role of ncRNAs in gene expression regulation will be elucidated


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Epigenetic programing of C.elegans lifespan
Funder: Wellcome Trust

Abstract: In the course of my PhD I would like to determine whether the various histone modifications and, hence, chromatin packing, change with age and what factors can affect this process. I would like to approach this topic using a non-biased approach of RNAi screen in C.elegans, Iwould also like to make an assessment of histone modification in ageing (somatic) and non-ageing' tissue using immunofluorescence and ChIP-seq. Furthermore, a use of faster and slower ageing mutants, as well as mortal germline' strain can be included in the study. The comparison of thoseepigenetic marks between somatic tissue and theoretically immortal' germline should provide some more cues that will help us to understand more about the ageing process, and perhaps provide new targets for future therapy


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Elucidating the molecular mechanisms of RNA localisation and translational regulation the role of ribonucleoprotein complex remodelling
Funder: Wellcome Trust

Abstract: The embryonic axes of Drosophila are established in the oocyte through regulation of translation of key localized transcripts including gurken (grk)/TGF-alpha. Localisation and translational regulation are achieved through remodelling of the composition of protein-RNA complexes during their transport. I propose to address the question of which key factorsare associated with grk and other axis specification mRNAs and how these are remodeled during nuclear export and transport in the cytoplasm. I will characterise the composition of such ribonucleoprotein (RNP) complexes at their point of synthesis and transport in living egg chambers using advanced live cell imaging. I will also address the role of known RNA-helicases in the remodeling of the RNP complexes in living mutant egg chambers. In complementary approaches, I will use biochemistry to determine the physical interactions that occur between the specific RNA binding proteins and their partner mRNAs. These studies will build on my unpublished data obtained during my rotation in the Davis lab, establishing anassay to covisualise grk and oskar mRNA with Staufen protein in the nurse cells. Furthermore, we plan to use existing methods and reagents already established and available in the Davis lab.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Role of non-muscle myosin II in Caenorhabditis elegans stem-like seam cell asymmetric division
Funder: Wellcome Trust

Abstract: Caenorhabditis elegans (C. elegans) stem cell-like seam cells undergo both symmetric and asymmetric divisions during larval development, thus providing a powerful system to study cell proliferation versus differentiation. The aim of my proposed research is to study how C. elegans seam cell asymmetric divisions are regulated. We have obtained preliminary data in which nmy- 2 was knocked down by RNAi, suggesting that a non-muscle myosin II-dependent mechanism may be responsible for ensuring proper seam cell asymmetric divisions. I will focus on the role of nmy-2 in this process, mainly by high-resolution microscopy and video lineage analyses of cell divisions in both RNAi-treated worms and mutant worms. Our early evidencesuggests that nmy-2 plays an important role in regulating seam cell asymmetric divisions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Development and application of approaches to study admixture, introgression and gene flow in wild mice and other organisms
Funder: Wellcome Trust

Abstract: Understanding the movement of genetic material between organisms and populations serves many purposes, such as highlighting genomic regions of particular biological importance or commenting on natural history and the relatedness of species and populations. The research proposed here aims to study said movement, beginning by studying introgression in subspecies of wildmice. Mice are of particular interest as they are a model organism which is used frequently for gene mapping studies; as such, understanding processes such as introgression will not only increase ourbiological understanding but also help us better interpret results from genetic studies in mice. Further work will include developing more advanced models and applying the methods developed for wild mice to otherpopulations and species, particularly humans and closely related species


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Transcription factors, cofactors and histone modifications changes at cis ]acting sequences during cell cycle
Funder: Wellcome Trust

Abstract: In the present project we aim to address the question of how transcription factors, cofactors and histone modifications change at cis-acting sequences (enhancers, promoters, boundary elements) during the cell cycle. Initially, we will simply assay DHSs whose presence is thought to reflect changes in nucleosome phasing associated with binding of protein to chromatin. We plan to investigate the changes at the á- globin locus in murine eythroleukemia cells (MEL), in G1, S, G2 and M stages. Identification of hypersensitive sites in erythrocytes will be achieved by using a DNase1 assay developed for high throughput sequencing. In order to achieve targeted, deep-coverage sequencing,in a time-efficient manner, the assay will be adapted for the IonTorrent platform.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE