NIHRDataInsights/HRCSData huggingface dataset:
Title: Mechanistic links between morphogenesis and differentiation
Funder: Wellcome Trust

Abstract: As cells build the body, they use information from localised secreted signals to guide differentiation and morphogenesis. It is often assumed there is unidirectional flow of information from these biochemical signals to the resulting morphological changes, but this 'linear' model cannot explain how development is orchestrated with such remarkable reproducibility. We have found that changes in epithelial structure provide a previously underappreciated source of information that feeds back into differentiation decisions by modulating biochemical signalling. Using mouse gastrulation as a paradigm we have identified candidate molecular mechanisms that mediate this feedback: 1) A cadherin-mediated community effect that dampens anti-neural signals to synchronise neural differentiation 2) a cell-clustering process that amplifies juxtacrine pro-mesoderm signalling to coordinate differentiation across collectives of cells. We propose that these two interlinked mechanisms coordinate distinct sources of information across different time scales. We will test this in vitro and in vivo using a unique toolkit based on molecular and biophysical manipulation of epithelial structure, mosaic analysis, and custom-developed quantitative image analysis software. Generalisable principles emerging from this work will help resolve the currently unpredictable relationship between "signalling-input" and "differentiation-output" to give us better control over in-vitro differentiation, organoid formation, tissue repair, and tumorogenesis.

Lay abstract: Cells build the body by a remarkable process of self-organisation. To do this, cells need to integrate multiple sources of information so that they make the right decisions in the right place at the right time. As they initiate differentiation cells change the way they stick to each other and consequently change the way they are organised in 3D space. We found that these changes influence subsequent differentiation decisions by making cells more responsive to "correctly placed" signals and less responsive to "incorrectly placed" signals. We now aim to identify the cellular and molecular mechanisms underlying this process. We will also test the prediction that these mechanisms help cells to avoid mistakes by imposing a short time delay to prevent cells from rushing too quickly into a decision (i.e. a "watch and wait" strategy) and by enabling cells to 'pool information' with their neighbours to ensure coherent and coordinated decision-making.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Serine ADP-ribosylation in genome stability and human disease
Funder: Wellcome Trust

Abstract: ADP-ribosylation (ADPr) is a post-translational modification (PTM) of proteins, synthesised by the poly(ADP-ribose) polymerase (PARP) family of enzymes. Through the modification of a variety of mediator/effector proteins, PARPs control cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the proteins involved in these pathways and their mechanisms of regulation remain poorly understood. Recently, we identified ADPr on serine residues in proteins (Ser-ADPr) as a previously unknown PTM. We showed that Ser-ADPr synthesis is dependent on histone PARylation factor 1 (HPF1), a recently identified specificity factor and interactor of DNA repair PARPs - PARP1 and PARP2. We further showed that Ser-ADPr specifically targets proteins involved in the maintenance of genome stability. Finally, we also revealed that a hydrolase called ARH3 acts as specific enzyme for a timely reversal of Ser-ADPr. Our first goal of this project is to use biochemical and structural approaches to understand the exact molecular mechanism by which HPF1 and ARH3 work in the synthesis/removal of Ser-ADPr. Our second goal is to define the physiological processes controlled by Ser-ADPr and to understand how these processes are regulated in cells, using cell biology approaches and animal models.

Lay abstract: Proteins perform the vast majority of biological functions within a cell. They can act as enzymes to catalyse reactions, as scaffolds to attract other proteins, as transporters and can replicate DNA. Proteins are what genes in DNA code for and their disruption and/or deregulation is implicated in a whole plethora of human disease, including cancer, neurodegenerative and autoimmune disorders. Importantly the control of protein functions occurs at many levels, including before (transcriptional regulation) and after (post-translational modification – PTM) a protein has been made. Our project is primarily focused on the PTM called ADP-ribosylation that is synthesised by enzymes called PARPs. PARPs are thought to control processes important for genome stability such as DNA repair and cell division. Our works aims to understand the exact mechanisms enabling timely synthesis and removal of ADP-ribosylation signals in cells and how these processes can be exploited in the treatment of human disease.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Translational Partnerships Award: 3 Year Renewal
Funder: Wellcome Trust

Abstract: Since 2018, the University of Edinburgh has been in receipt of a Wellcome Institutional Translation Partnership Award which has now been renewed for a further three years. The ambition of the partnership is to engage Wellcome Trust funded researchers and all of those working within the Wellcome Trust scientific remit, to identify and develop early stage translational opportunities within their research. Edinburgh embedded its scheme within Edinburgh Innovations building a small focused team, including two Entrepreneurs-in- Residence with a successful commercial/translational background to nurture projects towards translation through leveraging future funding, industry collaborations or commercialisation plus a dedicated Project Manager. Since inception, the program has engaged with hundreds of researchers, providing mentoring and support. Renewal of the award will allow access to translational support and funding across the University at scale. This will make beginning and navigating the translational journey for all researchers easier and increase the diversity of the translational portfolio both in terms of thematic area and forms of impact.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Global Cellular Controls in Fission Yeast
Funder: Wellcome Trust

Abstract: The major focus of the proposal is how CDKs ensure orderly progression through the cell cycle. The levels of potential CDK regulators through the cell cycle and their association with chromatin and the SPB will be determined to investigate cell size and ploidy monitoring mechanisms. The principle that cell cycle temporal ordering is established by differential CDK substrate sensitivity will be tested through multiplexed in vitro CDK and in vivo CDK assays, and by investigating different CDKs and CDK accessory proteins. The influence of cellular localisation on CDK activity will be examined by altering CDK location and through activity localisation assays. Using an in vivo single cell assay, the dynamics of CDK activity and its consequences on orderly cell cycle progression will be assessed and potential positive feedback mechanisms investigated. The phosphorylation changes that occur after TOR pathway inhibition will be measured at fine temporal resolution and correlated with changes in rates of RNA and protein synthesis, to investigate how overall cellular rates of synthesis are regulated. The mechanisms underpinning nuclear size homeostasis will be explored by testing the hypothesis that a major role is played by barrier membrane proteins that regulate membrane flow between organelles.

Lay abstract: Cells are the basic unit of life and we are investigating how they control their reproduction, their growth, and their internal spatial organisation. Cyclin dependent kinases (CDKs) are master regulators of cell reproduction. We will investigate how CDKs are controlled by cell size and DNA content, through monitoring CDK activities, the association of CDK with other proteins, and the locations of CDK and CDK substrates in the cell. Cell growth is regulated by TOR enzymes which phosphorylate a range of proteins. We will identify these proteins and determine whether they have effects on overall cellular protein and RNA synthesis. The size of the membrane bounded nucleus is tightly controlled, and we will investigate this control by studying membrane transfer in and out of the nucleus. All these processes are important for understanding how cells work, and are of relevance to certain diseases particularly cancer.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Clinical PhD Programme in Cancer Research
Funder: Wellcome Trust

Abstract: The Institute of Cancer Research (ICR), a degree-awarding, independent college of the University of London, proposes to host a Clinical PhD Programme in Cancer Research. The Clinical Fellows appointed to this Programme will be embedded in the highly successful translational research culture of the ICR, and our hospital partner the Royal Marsden Hospital (RM). Clinical Fellows will directly contribute to delivering practice-changing research and will be an integral part of the flow of ideas in both directions between the laboratory and the clinic. The Clinical Fellows will participate in, and learn from, research teams working as parts of global consortia on projects as diverse as understanding cell division, MR-guided radiotherapy, novel drug discovery and development; genome damage and stability and big data approaches. We will continue to maximise opportunities to support the career development of Clinical Fellows on this Programme; build on existing good practice in supporting clinical academics, strengthen the provision of training tools, workshops and mentorship opportunities; and facilitate communication and the establishment of collaborative relationships between ICR and RM clinical researchers at different career stages. The ultimate goal of the Programme is to train, develop and support future international leaders in clinical cancer research.

Lay abstract: No Data Entered

Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Epigenetic inheritance: establishment and transmission of specialised chromatin domains
Funder: Wellcome Trust

Abstract: DNA is a tape that carries the instructions for building all cell types in our bodies. DNA is packaged in the cell nucleus by wrapping it around spools made of histone proteins to make chromosomes. CENP-A is an exclusive histone that forms special spools at one region of each chromosome - the centromere. These CENP-A spools program construction of protein machines that ensure equal segregation of duplicated chromosomes into daughter cells during cell division. We aim to decipher the instructions that result in CENP-A spools being placed at particular positions on chromosomes. Heterochromatin is a structure formed when ordinary histone spools are clamped shut by particular chemical modifications. Heterochromatin near centromeres aids the placement of CENP-A spools. Heterochromatin is positioned at the edge of the nucleus. We will determine how heterochromatin is positioned at this location and if this location is important for directing CENP-A placement. Heterochromatin at other places on chromosomes controls which instructions are read and may allow the formation of different cell types. We will determine if heterochromatin forms sporadically and its role in generating cells with distinct characteristics. By understanding processes involved in constructing functional centromeres we will provide important information relevant to diseases including cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Mechanisms of epithelial polarity in flies and mammals
Funder: Wellcome Trust

Abstract: Apical-basal polarity is essential for all aspects of epithelial cell function and loss of this polarity is a hallmark of cancer. We have recently found that the endodermal epithelium of the Drosophila adult midgut polarises by a different mechanism from other Drosophila epithelia and may provide a good model for endodermal epithelia in mammals. This proposal aims to understand how polarity is generated in both epithelial types. Firstly, we will examine how the canonical polarity complexes polarise the secretory epithelium of the Drosophila follicle cells. We will investigate how Cdc42 is activated to define the apical domain; we will use optogenetics and super-resolution microscopy to investigate the dynamics and composition of polarity complexes; and we will analyse how cortical polarity organises the microtubule cytoskeleton through the lateral polarity factor, Par-1. Secondly, we will perform clonal screens to identify essential epithelial polarity factors in the Drosophila midgut and characterise their functions. To test whether these factors play conserved roles in mammals, we will knock out their orthologues in mouse intestinal organoids. This research will reveal the fundamental mechanisms that polarise different epithelial types, which is an essential prerequisite for understanding epithelial function and how it is perturbed in diseases like cancer.

Lay abstract: Most of our organs are composed of sheets of epithelial cells that function as barriers between compartments (e.g. blood vessels) or between the inside and outside of the body (digestive system). The formation of epithelial sheets depends on the coordinated polarisation of the cells, so that all have their apical surfaces facing the outside, but this polarity is disrupted in cancer. My research programme aims to determine the mechanisms that polarise epithelial cells. There are at least two types of epithelia that polarise by different mechanisms, and we will study an example of each type in the fruit fly, so that we can exploit the sophisticated genetics of this system. We will perform genetic screens to identify mutants in polarity factors, and combine advanced imaging with genetic manipulations to analyse their functions. We will then use mouse intestinal organoids to test whether these polarity factors play conserved roles in mammals.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Wellcome Trust Centre for Surgical and Interventional Sciences
Funder: Wellcome Trust

Abstract: Image-guided Intervention (IGI) has enabled greater surgical precision resulting in reduced tissue trauma, co-morbidity, complications, and hospitalisation time. However, significant limitations arise from the challenging use of IGI systems, and their predominant reliance on preoperative anatomical images. Disrupting existing IGI, we will deliver pathologically, anatomically, and physiologically optimal surgery by combining diagnostic-quality imaging/sensing with ergonomic smart instruments. The Wellcome Trust Centre for Surgical and Interventional Sciences (WTC-SIS) will launch a new phase in which anatomical cues, which have driven interventional therapies for centuries, are augmented by physiological and pathological insight. Three fundamental research themes will link the WTC-SIS interdisciplinary groups: Physiological navigation, focusing on fusing anatomical, physiological and pathological information for real-time guidance/monitoring. Clinician experience, focusing on optimising the clinical team cognitive/ergonomic workload. Precision instrumentation, focusing on designing interventional devices that both sense physiological/pathological information and interact with tissue. WTC-SIS will serve as a hub-and-spoke translational catalyst for indication-specific externally-funded projects across surgical domains. A single unified Centre (hub) will provide all relevant skills and know-how, from scientific expertise to good manufacturing principles. This will drive rapid translation in our clinical satellites (spokes) and industry engagement through the development of a Health Technology Assessment programme.

Lay abstract: No Data Entered

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Regulation of and signal transduction pathways from cell-cell adhesions
Funder: Medical Research Council

Abstract: Cell-cell adhesions complexes are crucial for the assembly of individual cells into three-dimensional tissues. However such complexes are not just glue connecting neighbouring cells, they also have a positive role in constructing diverse and intricate forms of tissues and are dynamically regulated, during cell migration and differentiation for example. Furthermore, cell-cell adhesion complexes are involved in many other processes, such as cell polarity, proliferation, differentiation, and apoptosis. It has also been realized that the loss of epithelial differentiation in carcinomas is often a consequence of reduced intercellular adhesion and indeed some components of cell-cell adhesions function as tumour suppressor proteins (e.g. E-cadherin). The goal of my research group is to answer the following questions centred around cell-cell adhesions: How are cell-cell adhesions dynamically regulated? What molecular mechanisms are involved in disrupting cell-cell adhesions? How do cell-cell adhesions modulate signal transduction pathways controlling proliferation and differentiation?||We recently revealed that specific phenomena are observed at the interface between normal and RasV12-transformed epithelial cells (Hogan et al., 2009, Nature Cell Biology). In the majority of cancers, transformation occurs in a single cell within an epithelial cell sheet. However, it is not known what happens at the interface between normal and transformed cells once the initial transformation has occurred. Using MDCK epithelial cells that express oncogenic Ras (RasV12) in a tetracycline-inducible system, we have investigated the cellular processes arising at the interface between normal and transformed cells. We show that two independent phenomena occur in a non-cell-autonomous manner; when surrounded by normal cells, RasV12 cells are either apically extruded from the monolayer, or form dynamic basal protrusions and invade the basal matrix. Neither apical extrusion nor basal protrusions are observed when RasV12 cells are surrounded by RasV12 cells. We show that Cdc42 and ROCK play a vital role in these processes. We also demonstrate that E-cadherin knockdown in cells surrounding RasV12 cells reduces the frequency of apical extrusion, while promoting basal protrusion formation and invasion. These results indicate that RasV12-transformed cells are able to recognise a difference with normal cells and consequently leave epithelial sheets either apically or basally in a cell-context-dependent manner.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: The Role and Regulation of Tiam1-Rac Signalling in Bipolar Spindle Assembly
Funder: Medical Research Council

Abstract: Previously we showed that Tiam1 and Rac regulate centrosome separation and mitotic spindle function. Now, our latest data imply that phosphorylation of Tiam1 on S1466 by CDK1/ cyclin B is required for these functions. We have generated S1466A and S1466D mutants and shown these to be functionally inactive and effective respectively, and have produced a phospho-specific antibody to this site which shows a CDK1-dependent increased signal in mitosis. Our experimental plan takes advantage of the knowledge and tools we have generated so far, beginning with the use of our phospho-specific antibody to analyse the spatial and temporal dynamics of S1466 phosphorylation by immunofluorescence and/or biochemistry. We also plan a series of experiments to examine further the role of Tiam1 and Rac in regulating microtubule stability, and will use our phospho-mutants to directly link the phosphorylation of Tiam1 to this mechanism. An important part of our experimental plan is to identify other proteins involved in the mitotic Tiam1/ Rac signalling pathway; specifically, proteins which preferentially bind to the S1466 phosphorylated form of Tiam1. For this we will adopt both a global approach, using our S1466D and S1466A mutants in a mitosis-specific mass spectrometry experiment, and a candidate approach, by selecting particular proteins from the literature and/ or previous interactor screens as likely candidates. Candidate proteins will be tested firstly for potential interactions with Tiam1 in transient co-immunoprecipitation experiments, then functional experiments will be performed on successful candidates using a combination of techniques. Finally, we aim to take advantage of our close relationship with the breast pathology lab of Prof. Goran Landberg to investigate the phosphorylation status of Tiam1 in breast tumours, as well as investigate the effect of modulation of this signalling pathway on the sensitivity of breast cancer cells to treatment with anti-microtubule drugs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Structural and mechanistic studies of the breast cancer tumour suppressor BRCA2 in DNA double strand break repair
Funder: Medical Research Council

Abstract: Since its discovery, the breast cancer tumor suppressor brca2 gene and the 3418 amino acid protein it encodes (BRCA2) have been the subject of intense study. BRCA2 plays important roles in homologous recombination, the main mechanism in error-free homology directed DNA double strand repair during the S and G2 phases. Human BRCA2 is one of the largest proteins in the cell. The large size and low abundance of BRCA2 made it extremely challenging to purify the full length protein, which has hindered its biochemical, structural and mechanistic characterization. However, very recently, three groups including that of dr Stephen West, have reported the purification and biochemical characterization of BRCA2, creating an exciting opportunity for structural studies. In this proposed research, we will employ biochemistry expertise in dr Stephen West's laboratory and electron microscopy single particle analysis technique in Prof. Xiaodong Zhang's laboratory in combination with protein homology modeling and algorithms development in dr Paul Bates group for fitting crystal structures into low resolution EM reconstructions. Together we will characterize the structures of BRCA2 alone and its complexes with RAD51 and PALB2 in order to provide a molecular basis for its roles in DNA double-strand break repair. The information obtained will not only provide us with the first glimpse of the structures of this important protein and its interacting partners, but also reveal insights into how BRCA2 helps to load RAD51 onto single stranded DNA that eventually leads to strand invasion and homologous recombination. This will constitute a significant step towards our understanding of this key cellular process that has a direct link to cancer and aging. It will improve our knowledge about the cause of the disease and also offer opportunities for novel therapeutic approaches for DNA damage repair mechanisms .


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS