NIHRDataInsights/HRCSData huggingface dataset:
Title: Plk1 regulation of chromosome segregation and the mitotic spindle
Funder: Wellcome Trust

Abstract: Bipolar spindle formation and chromosome alignment are essential and tightly regulated mitotic processes. Misaligned chromosomes can lead to missegregation and create aneuploidy and genetic instability, a characteristicassociated with cancer cells. Polo-like-kinase-1 (Plk1) is a serine/threonine kinase with multiple mitotic functions from centrosome maturation to chromosome alignment and cytokinesis. Many substrates have been identified, yet the molecular mechanism underlying Plk1-induced centrosome separation and spindle assembly remains unclear. Preliminary results from the Welburn lab suggest that Plk1 regulates microtubule dynamics and microtubule length in mitosis. In addition, the data indicates a role of Plk1 in bipolar spindle formation independent of Eg5, which may involve Plk1-dependent activation of dynein to induce centrosome separation. To show this I will (1) perform a targeted mitotic screen to identify Plk1 substrates (2) test if Plk1 localization is important for mitotic function. Toaddress this question, I will alter the Plk1 localisation to microtubule plus


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Modelling wound re-epithelialisation in Drosophila embryos.
Funder: Wellcome Trust

Abstract: Epithelial wound healing is crucial for the survival of every organism. Following injury, tissue integrity is restored by conserved mechanisms, which require collaborative efforts by several different tissues and all lineages. Aberrant wound healing can lead to several human pathologies, such as chronic wounds and scarring, with treatments remaining crude even today. I want to further understand the molecular mechanism underlying wound healing, focusing on the clear but poorly explored role of changing tensions during tissue repair, microtubule function during wound repair, and the role of new wound up-regulated genes in the epithelium. To answer the questions how cells sense mechanical strains and what subsequent downstream signals they activate after experiencing mechanical force, I will express several different tension reporters in the epithelium of stage 15 embryos and live image them after wounding by laser ablation. Additionally, I plan to use a tissue micromanipulation assay as well as RNAi and mutant studies. By using correlative light microscopy, as well overexpression of a microtubule severing protein and mutant analysis, I will test how microtubules contribute to wound repair. By using data from a recent microarray analysis, I will try to find new key players important for re-epithelialisation after injury.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Signalling Interactions of the Syndecan-4 Cytoplasmic and Extracellular Domain.
Funder: Wellcome Trust

Abstract: Syndecan-4 is a transmembrane heparan sulphate proteoglycan (HSPG) which has akey role in wound repair. Syndecan-4 is known to influence cell behaviour in the wound bed through interactions of both its ectodomain and transmembrane protein core. The goal of this project is to determine how the functions of the syndecan-4 intra- and extra- cellular regions are integrated to relay signals from the extracellular matrix (ECM) to cytoplasmic effector molecules during wound healing. Syndecan-4 engagement leads to the activation of multiple small Rho GTPases, such as Racl, which act to modify cytoskeletal dynamics (Brooks et al, 2012). Preliminary work has shown that syndecan-4 activates the guanine exchange factor (GEF) Vav2, which then activates Racl. I have shown that Vav2 is cleaved in response to syndecan-4 activation. We hypothesise that proteolytic cleavage presents a novel mechanism for Vav2 regulation, and plan to identify the physiological function of this cleavage. Soluble syndecan-4 is released from the cell surface into wound fluid by sheddases. How this fragment modulates signalling from the ECM to impact migratory processes is unknown. We plan to produce syndecan-4 proteoliposomescomplexed with various ligands to assess the contribution ofthis domain compared to full length syndecan-4 to signalling, and to correlate this signalling function to polarised shedding.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Cyclin B1, critical regulator of the timing of cell division.
Funder: Wellcome Trust

Abstract: A critical aspect of the cell cycle is the maintenance of high levels of cyclin B1 at metaphase followed by its rapid APC driven destruction as chromosomes segregate. Impaired regulation of cyclin B1 at this stage of the cell cycle is firmly associated with aneuploidy. Knowledge of cyclin B1 control is largely limited to studies in mitotic cells. Here I will address for the first time whether mechanisms differ between mitosis and meiosis. Indeed preliminary data provide strong evidence to sugges t vastly differing regulation and have therefore led to the design of experiments to fully characterise this. Specifically; to determine how cyclin B1 is recognised by the meiotic destruction machinery and to detail the mechanistic implications of differential spatial control of both cyclin B1 and the APC in meiosis and mitosis. Differential cyclin B1 control mechanisms ultimately point towards the existence of meiosis specific APC activator. A key goal of this project will be to uncover its identity and detail a role in both vertebrate and invertebrate meiosis. A full understanding of the physiological process which regulate cyclin B1 and metaphase exit is important since errors are not uncommon and have a great negative impact on human health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Systems microscopy analysis of centrosome maturation in living cells.
Funder: Wellcome Trust

Abstract: The proposed research is to study living human cells with state of the art light microscopy in order to understand how they are able to reproduce. The molecular machines which allow cell division are formed from many different molecular building blocks. I will for the first time systematically identify and observe all of the parts which are required to make one particular structure inside the cell which has an important role in cell replication, called the centrosome. Firstly I will create a com prehensive list of parts which form the centrosome, by detailing where inside the cell several hundred of its different molecular parts are located, and by measuring precisely how fast they dynamically move. Secondly I will understand how the parts of this molecular machine build a structure by discovering which of them physically fit together.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: A novel multidisciplinary approach to interrogate the impact of cell polarisation events on pluripotent cell fate decisions.
Funder: Wellcome Trust

Abstract: In order to shape the embryo, cells need to accomplish at least three functions: -Multiply for the embryo to grow. -Make a decision of becoming a particular cell type (differentiation) -Adopt a specific shape in a coordinated fashion with its neighbours so that various architectures can be created, such as vessels or walls. It is generally thought that cells make the differentiation decision first and then create different architectures according to their decision. However, the sequence o f event is not clear and it might be that the initial organization of cells plays an instrumental role in guiding cells to make their differentiation decision. It will be important to test this. Indeed, we still do not fully understand how cells diversify in such a coordinated way during development and the effect of cell architecture has been overlooked. To address this challenging question, we have designed unique tools to carefully monitor both the collective organization of the cells and their differentiation choices. We have also designed experiments to control the way cells organize in order to understand how different architectures may regulate differentiation. This study will help us understand development and to generate useful cell types for cell therapy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: In vitro reconstitution of spindle bipolarity.
Funder: Wellcome Trust

Abstract: In order to understand how something works and evaluate which parts are absolutely essential for it to function properly, one strategy is to take it apart and then try to put it back together from the components one suspects it is primarily made of. Here I propose to use this type of approach in a new way to find out what exactly is required to form a sub-cellular structure called the mitotic spindle. The spindle carries out an all-important task of dividing the genetic material equally between the daughter cells during cell division and errors in its function contribute to cancer development. Although most of the molecular building blocks of the spindle have been identified, we still do not know how they work together to assemble into such a complex architecture. To address this key question, I will first isolate these components and then combine them in various ways to build spindles in a test tube. This way, I aim to show directly how these structures form and which elements are abs olutely necessary to assemble proper spindles of correct shape and size instead of faulty ones that would not be able to segregate the genetic material accurately in the cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating the consequences of genetic variation on protein-protein and protein-ligand interactions.
Funder: Wellcome Trust

Abstract: This bioinformatics research project will focus on investigating the structural and functional consequences of genetic variation on protein-proteinand protein-ligand interactions. The project will build on a variety of reference structural and genomic datasets and will involve large-scale mappingof structural interaction interfaces from known and inferred structural complexes. This will be followed by thorough characterization and mapping of non-synonymous single nucleotide polymorphisms (nsSNPs) onto structural interaction interfaces. Machine learning techniques will be applied to the generated data to develop new prediction methods made available as integrated web-resources. The new resources will be applied to novel whole exome and genome datasets produced by colleagues in Dundee with the aim of better characterizing and identifying relevant disease-associated nsSNPs to prioritize experimental validation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Between patient autonomy and physicians responsibility to save life: The implementation of advance directives in three European countries (England, France, and Germany).
Funder: Wellcome Trust

Abstract: This study will explore how different cultures and practices influence legislation, practical guidance and moral viewpoints on advance decision-making in England, France and Germany. For this purpose I will analyse both theoretical approaches to ADs and concrete practices. By reviewing theoretical literature, I will first identify principal actors, their arguments and the influence they exert on the formulation of the questions regarding ADs in each country. In order to get to know implementatio n of ADs and concrete experiences of situations, the project involves observations of everyday life in hospitals and interviews with professionals considering problems associated with decisions to withdraw treatment in general and more specifically for patients who cannot express their will anymore. The observation of medical practices and interviews with professionals shows the gap between what doctors think is important and what they actually do in a concrete situation. This may reveal general norms as well as cultural, legal and historical particularities in a certain country and help us to rethink theoretical concepts and define recommendations that are better suited to the reality in each country.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Clinical PhD Programme at the University of Edinburgh: "Exploration of Helminth-derived immunoregulatory molecules as options for cellular or pharmacological intervention in transplantation"
Funder: Wellcome Trust

Abstract: Helminth worms are particularly successful parasites that currently manage to infect more than a quarter of the world's population. They manage this by effectively dampening down the immune system of their host by a number of mechanisms This dampening effect makes itdifficult to clear the helminth infection, but may also provide a number of benefits. The presence of a helminth, or it's secretions, does appear to protect the host against diseases where the immune system is over-active or attacking the body's own tissues. Recent studies have shown a reduction in the severity of disease in animal models of asthma, multiple sclerosis, inflammatory bowel disease and diabetes. With this project, our aim is to assess whether helminths and their secretionscan protect transplanted organs against rejection from the recipient patient's immune system and, if so, to establish which mechanisms and/or molecules are involved so that new treatments can be designed. This would offer considerable improvement over current medications that are used for transplant recipients, which are imperfect at preventing organ rejection and also put patients at risk of numerous side-effects including infection and cancer.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE
Title: Fostering Appropriate Questioning and Well-placed Trust in the Acute Care Setting: Developing an Ethical Framework and Practical Policy.
Funder: Wellcome Trust

Abstract: For good clinical care to be delivered, patients need to trust their doctor, particularly when admitted to hospital acutely ill. Too much, or poorly-placed trust, however, might not be beneficial. I will explore what well-placed trust is in the acute setting and consider the links between information sharing, communication, trust, and asking questions. I will explore, with clinicians and patients, if and how help in asking relevant questions, and written communication for patients, might fa cilitate trust and improve care in the acute setting. I will combine ethical analysis, interviews with patients, doctors and nurses, and a questionnaire survey. There will be three interlinked research strands 1. A critical review of academic papers on trust and communication followed by ethical analysis 2. Interviews with patients, doctors, and nurses exploring: - their experience of trust and patient-doctor communication in the acute setting - what they think might improve comm unication and trust in this situation 3. Questionnaires will be developed using case scenarios, which will be sent to a larger number of patients and clinicians. Finally I will use this information to develop a practical policy for patient-doctor communication with a proforma for sharing written information with patients in the acute medical setting.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Human Adaptation to Changing Diet and Infectious Disease Loads, from the Origins of Agriculture to the Present.
Funder: Wellcome Trust

Abstract: Modern patterns of human health and disease have been shaped by cultural, demographic and ecological changes over the last 10,000 years, particularly in association with the transition to agriculture and subsequent increases in urban settlement, population density and mobility, and reduction in dietary breadth to a few key staples. These changes will, in turn, have led to increased carbohydrate consumption and glycaemic loads, infectious disease loads, and the potential for zoonotic transmission . Natural selection will have acted upon human genetic variation in response to these changes, particularly that involved in diet and infection, and the detection of signals of natural selection provides a clear-cut means of identifying medically-relevant genetic variation in past populations, since it identifies variants that affected survival. While many methods and studies have been aimed at detecting recent natural selection, none can be as sensitive as the direct comparison of allele freque ncies at different time points in continuous human populations. Furthermore, this approach is currently the only means of assessing temporal heterogeneity in natural selection. We propose to quantify the tempo and extent of evolutionary response to infectious disease loads and dietary change in Europe by applying a candidate gene, high-throughput capture-based approach to both archaeological and modern samples. We will also integrate archaeological and historical data to assess the impact of key transitions in diet, demography, economy and settlement on health.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Membrane Protein Folding and Disease: Molecular Mechanism via Simulation
Funder: Wellcome Trust

Abstract: The goal of the work is to address the research questions on membrane protein folding above, using molecular simulation as a tool to provide insight into the folding pathways. The reasoning behind this approach is that we can use anunderstanding of folding and misfolding mechanisms at a molecular level to design novel therapeutic strategies against protein misfolding. Novel coarse-grained models will be developed in order to make it possible to sample membrane protein folding events. Simulations with these models will be used to identify folding pathways and intermediates. By investigating the effect of mutations (or lipid composition) on these pathways, and on misfolding, we hope to generate new insights into the key ("gatekeeper") residues for preventing membrane protein misfolding. The results will be benchmarked as far as possible against experiment. In addition to the above approach which considers only the spontaneous foldingof membrane proteins, the model(s) could be extended (time permitting) to include the role of the translocon, and the rate of protein synthesis, to form


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: High-Throughput Electroporation of Primary Cells
Funder: Wellcome Trust

Abstract: We are requesting funds for the purchase of the Cellectricon CellAxess Elektra to facilitate high-throughput screening projects in primary and iPS cells at University College London. The Cellaxess Elektra is a unique fully automated electroporation instrument that enables the transfection of primary cells in a high-throughput experiment. Currently, there is no such instrument in the UK and there are very few in academic institutes in Europe. Our in house tests have demonstrated that the CellAxes s Elektra is superior to any other HTS electroporation device and the only high-throughput electroporator on the market that works reliably for primary neurons, macrophages and iPS cells. Therefore CellAxess HT will make it possible to perform high throughput screens using iPS cells, macrophages, neurons and other primary cells opening new research avenues in neuroscience, virology and stem cell research. Within the Translational Research Resource Centre, the Cellaxess Elektra will be available to multiple research groups at UCL with the main aim to facilitate cross-faculty research collaboration, generate novel lines of research and promote translational research that aims at identifying novel drug targets and compounds for potential commercial exploitation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: A direct electron detector for electron cryo-microscopy.
Funder: Wellcome Trust

Abstract: The field of electron cryo-microscopy (cryo EM) is playing an increasingly important role in structural molecular and cellular biology, owing to advances in hardware and software that improve the image quality and facilitate the work. A major limitation has been the low quality of image recording, because of the low contrast and high radiation sensitivity of biological samples. Digital detectors are essential for high-throughput data collection, but the commonly used CCD detectors have worse res olution than photographic film. They convert electrons into visible light for signal recording, and this conversion degrades the image quality. Recent developments have led to commercially available direct electron detectors giving far superior performance for EM, with excellent test results already published. They provide information to the theoretical limit of resolution, whereas CCD images lack the higher resolution details. The signal/noise ratio of direct detectors at maximum resolution is at least 10-fold superior, providing major advantages for both single particles and cryo tomography. Since cryo EM operates at the limits of detection for delicate biological structures, this instrumental advance makes a vast difference to feasibility, resolution and efficiency of data collection. The resulting improvements in biological output lead to a much better use of expensive facilities.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms of R-loop formation in mammals: Interplay with RNA polymerase II regulation and epigenetic modifications.
Funder: Wellcome Trust

Abstract: Transcription is the first step of gene expression in which a specific part of DNA (the molecule that carries the genetic information) is copied to RNA by the enzyme RNA polymerase. Although the structure of the DNA is arranged as double helix, only one strand (template) is copied into RNA. Since the RNA possesses complementary base pairs to the template DNA strand, RNA can invade the DNA duplex and pair with the template DNA strand. This formed structure is called an R-loop. For years R-loop s were thought to lead to damage of the DNA structure and potential cell death. In contrast I plan to investigate the positive roles of R-loops in transcription. I aim to study how R-loops may regulate the transition of cells from early developmental stages to their final ones. To better understand how R-loops may control the transcription process, I plan to study the role of R-loops in the context of how transcription begins and ends. To address this I intend to also study modifications that d o not rely on the DNA sequence (epigenetic modifications). Finally I will investigate what is the function of RNA polymerase in the establishment and action of R-loops.


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