NIHRDataInsights/HRCSData huggingface dataset:
Title: Coupling the molecular motor Kinesin-1 to new cargo, functions and diseases.
Funder: Wellcome Trust

Abstract: Cells possess specialised components that must be in the right place at the right time to fulfil their function. After their use, these components must be transported away for recycling or degradation. Disruption of these transport processes can contribute to many human diseases such as neurodegenerative disorders or cancer. To move components around, cells use a transport system composed of a network of cables known as the microtubule network. Much like a railway network, these cables link tog ether regions of the cell. Cells possess vehicles that travel along this network known as molecular motors, of which my proposed molecule of study, kinesin-1, is one of them. These motors can selectively attach to cellular components and move them on the microtubule network. Here I propose to determine what components the molecular motor kinesin-1 attaches to and how it does it. In particular, I will focus on studying those components that are involved in human diseases as in the long term, I be lieve that manipulating the transport of cellular components may be a way to treat human diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Dissecting the molecular mechanism of a group II chaperonin: protein folding in the thermosome and role of prefoldin.
Funder: Wellcome Trust

Abstract: All the major functions of the cell are performed by proteins, including movement, the generation of energy, growth, division, and signalling. After their synthesis, protein chains have no biological activity until they fold up into precise shapes. In the cell, a group of helper proteins, known as molecular chaperones, has the function of assisting the process of folding of newly synthesised polypeptides to their biologically active structure. Among these, the chaperonins are cavern-like, toroid al structures capable of capturing unfolded, aggregation prone protein chains and sequestering them in a central cavity, where they can spontaneously fold into their native, functionally active structure in a protected environment. The group II chaperonins are those found in eukaryotic cells and in archaea, and this project aims at understanding how the thermosome, an archaeal group II chaperonin, works in conjunction with prefoldin. This co-protein delivers the unfolded polypeptide to the ther mosome, that engages in a cycle of binding and swallowing it into a cavity, closing the cavity to allow folding in a protected space, re-opening and ejecting the folded protein into the cell. The elucidation of these steps will lay the groundwork for understanding the molecular machinery that assists protein folding in the cell.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Statistical methods for understanding the genetics of human disease phenotypes.
Funder: Wellcome Trust

Abstract: Recent advances in technology have meant that scientist can collect genetic information on a large number of individuals and correlate their DNA with specific diseases. This simple approach to identifying genes has been successful in elucidating some of the genetics of many common diseases, with the hope that the new understanding will help in treatment and prevention. However, there is now an exciting opportunity to push this research even further. By looking at new populations, combining data across populations, or comparing data across multiple diseases we are likely to identify new susceptibility genes. Perhaps more interestingly, by comparing and contrasting studies, we can begin to understand the biological mechanisms that link different diseases and those that set them apart. The aim of my research is to help enable scientist to conduct these new studies, by developing innovative methods, through the process of studying the genetics of specific diseases, such as malaria and multiple sclerosis.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Functional Consequences of Synonymous Mutations in Eukaryotic Cells.
Funder: Wellcome Trust

Abstract: In order to survive and grow, cells need to decode the information written in the genome. The genetic code , which specifies how the information in the DNA is used to make different proteins, was solved in the 1960s. In contrast, the regulatory code , which determines the amount of each protein produced, is still very poorly understood. If we can understand the regulatory code, we will be able to predict the effects of different DNA mutations on protein amounts in the cells. This information c ould be used, for example, to understand the mechanisms of various diseases, or to artificially manipulate the amounts of proteins made by genes. I plan to study the regulatory code, and how it differs between different organisms and different external conditions. I will do that by measuring the amounts of proteins produced by thousands of mutant genes, and using computational methods to tell which mutations were most likely to produce an effect on protein production. I will then confirm thes e statistical predictions experimentally. These experiments will increase our understanding of how the human genome works, and they may lead to practical applications in bio-medicine.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating the molecular mechanisms of Minute competition in Drosophila.
Funder: Wellcome Trust

Abstract: Cell competition is a process, which allows the elimination of less fit cells albeit viable cells by a fitter cell population in the same tissue. This may act as a quality-control to eliminate suboptimal cells. Cell competition can be triggered by differential activity in several genes, such as ribosomal subunits or myc levels. Despite its discovery 37 years ago the molecular mechanisms of this phenomenonare largely unknown. This project aims at identifying the genes responsible for the early recognition event between winner and loser cells, which trigger cell competition. Our strategy will be three-fold: 1) We will identify genes differentially expressed between winner and loser cells by transcriptional profiling. 2) We will select a list of about 200 differentially expressed candidate genesand perform an RNAi-based secondary


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Function and evolution of the atypical Notch ligands Dlk1 and Dlk2 during vertebrate development.
Funder: Wellcome Trust

Abstract: Delta-like homologue 1 (Dlk1) is a vertebrate-specific atypical Notch ligand involved in development of multiple lineages in mouse. Genetic studies have shown it to be a key regulator within several pre and postnatal stem cell niches. Murine Dlk1 encodes soluble or membrane-bound protein isoforms depending on the presence of a juxtamembrane protein cleavage site, removed inalternatively spliced transcripts. Deciphering the signaling mechanisms of Dlk1 and the different functions of the Dlk1 isoforms has been very challenging in mouse. Zebrafish (Danio rerio) is an ideal model system to elucidate the fundamental aspects of Dlk1 function due to the relative ease and availability of molecular tools and techniques. In addition, Dlk1 in zebrafish is missing the juxtamembrane motif, whereas a closely related vertebrate-specific gene Dlk2, retains it, suggesting that zebrafish may use adifferent mechanism to produce membrane-bound and soluble Dlk, fulfilled by Dlk1 and Dlk2 respectively. Such proposed gene-specific functions make zebrafish a tractable model to decipher the specific roles of the secreted and


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Functional and molecular characterisation of Bod1L.
Funder: Wellcome Trust

Abstract: The goal of my research is to determine the function and mechanism of action of Bod1L, a novel 330 kDa protein that shares homology to the PP2A inhibitors Bod1, Arpp-19 and Ensa. During my rotation work I showed that Bod1L, a protein related to Bod1, acts to modulate the localisation of MDC1 at the double strand break (DSB) repair foci and is required for efficient repair of DSBs. Upon siRNA depletion of Bod1L, cells progressed through mitosis with unattached, acentric, fragmented chromatin and showed increases in MDC1 protein levels at break sites. This phenotype was rescued by the co-depletion of PP2A-B56. This evidence and other concurrent work led to the hypothesis that Bod1L is acting as a novel PP2A-B56 inhibitor, the function of which is critical in controlling the proper repair of DNA damage and dissociation of MDC1 from DSBs. This research proposal aims to explore this further by addressing three principle aims. Firstly, to test the hypothesis that Bod1L functions through an interaction with PP2A-B56. Secondly, to investigate the binding and interaction of proteins with Bod1L and thirdly, to determine how Bod1L and PP2A-B56 affect DSB association of key repair components. I will explore these hypotheses using a combination of proteomic analysis, biochemistry and microscopy techniques.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Computational Prediction of the Effects of Non-Synonymous SNPs on Protein Function
Funder: Wellcome Trust

Abstract: This bioinformatics research project will focus on the development of methods to predict the effects of non-synonymous single nucleotide polymorphisms on protein function. The project will evaluate current methods, develop a "meta-predictor" that combines the best methods and develop a new approach that includes data from recently published techniques in protein structure prediction and sequence analysis. The new predictor will be integrated with the Jalview multiple alignment workbench and be applied to novel whole exome and genome datasets produced by colleagues in Dundee.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Non-canonical pathways for regulation of AMPK.
Funder: Wellcome Trust

Abstract: Previous work by Prof. Grahame Hardie, supported by the Wellcome Trust, showed that cells (the fundamental units from which all living things are made) in humans, animals, and plants contain a system called the AMPK complex. AMPK senses the energy status of the cell, analogous to the systems in mobile electronic devices that monitor the battery charge. If AMPK senses that energy status is compromised, it switches on the uptake and metabolism of nutrients, such as glucose and fats, to restore cel lular energy, while switching off processes that consume energy, such as cell growth and division. Because of these effects, drugs that switch on AMPK have already proved useful in treatment of diabetes and cancer. Recent research has suggested that AMPK is modulated by inputs other than cellular energy state, such as agents that promote cell growth, levels of nutrient stores, treatments that damage DNA (cytotoxic drugs used in cancer treatment, radiation, and oxidants generated by oxygen metabo lism) and salicylate, a breakdown product of aspirin. However, the mechanisms by which these treatments modulate AMPK are not as well understood, and the project will investigate these. The research could suggest new approaches for treatment of diabetes and cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Public health and outsiders': British responses to refugees in the twentieth century.
Funder: Wellcome Trust

Abstract: This project uses public health policy towards refugees as a way into understanding the nature of health citizenship and belonging in twentieth century British society. In doing so it will reveal how different population groups were received by the British state and public in the twentieth century, and offer insights into the public health challenges involved in receiving refugees into the UK. Using four case study groups - refugees from Nazism in the 1930s; Displaced Persons relocated to Britai n after 1945; Ugandan Asians in the 1970s and post-1991 refugees/asylum seekers - the research will show what public health policy towards refugees looked like at different levels of the state at different times. It will ask how policies such as internment camps and medical examinations affected both the health of refugees and their experiences of a liberal British state. Through pubic engagement initiatives, including articles, blogs and a round table event, the project will provide policy make rs with vital historical context in order to inform present policy dilemmas.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Synchronization of Cilia.
Funder: Wellcome Trust

Abstract: Throughout our body, and from embryonic development to adulthood, cilia play crucial roles in physiology. This proposal aims to understand the physical and biological mechanisms that underlie the often striking coordinated movement found in the beating of groups of interacting cilia. These patterns of coherence range from precise synchronization of nearby pairs to metachronal waves in which there is a large-scale modulation of the beating dynamics, as found in the respiratory and reproductive systems Such coordinated motion is often crucial to the biological functions of ciliary arrays. Our research will take advantage of recent experimental advances we have made in high-speed imaging and time series analysis of ciliary dynamics to study the interrelationship between fluid mechanical interactions between beating cilia and the underlying molecular aspects of waveform generation. This is done using as model organisms a lineage of unicellular and multicellular green algae whose fla gella are nearly identical to the cilia in humans and whose beating dynamics can be studied in unprecedented detail.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Ethics of patient safety and quality in healthcare.
Funder: Wellcome Trust

Abstract: The study of ethical issues in both delivering and researching patient safety and quality (PSQ) in healthcare remains seriously underdeveloped. My goal, using a robust programme of applied empirical research and normative analysis, is to advance the field by identifying and characterising the moral dilemmas in seeking to provide safe, good quality care, and to generate principles and moral rules to help guide analysis and resolution of these challenges. I will produce a critical understanding of the institutional structuring of patient safety and quality activities, including penetration of the field by new players who claim expertise, jurisdiction and authority, and the institutional logics that direct attention towards specific problems and solutions. I will identify the normative basis of different kinds of interventions designed to improve safety and quality, including those such as financial incentives and technology that intervene in professional discretion. I will produce a cr itical, empirically informed account of accountability systems, including the ethical issues raised by using administrative and clinical data as a means of staff surveillance and discipline. I will develop a framework for ethical analysis that can be applied to the evaluation of safety and quality interventions, and thus help to settle ambiguities about which innovations require evaluation, which form of ethical review should apply, and the moral status of healthcare workers as research particip ants. My research will inform the optimal design and selection of strategies for securing patient safety and quality, while being sensitive to the trade-offs and tensions between different values, goals, and interests.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Cambridge Stem Cell Institute Four year PhD studentships - Stem Cell Biology. Animal Supplement - Moritz Matthey
Funder: Wellcome Trust

Abstract: RESEARCH ABSTRACT QUESTION ONLY Increasing awareness and understanding of the promise and challenges of stem cell research is embedded in the Stem Cell Institute vision and summarised in one of five strategic goals: Communication and public engagement providing reliable information, useful resources, and dialogue opportunities for a range of audiences including schools, policy makers, patient groups, professional bodies and the media Accordingly SCI aims to promote and engage in public dialogue relating to stemcell science. The high level objectives of these public engagement activities are to contribute to: sustaining public support for stem cell research and science in general informing and influencing public policy encouraging uptake of careers in STEM subjects


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Cambridge Stem Cell Institute Four year PhD studentships - Stem Cell Biology. Animal Supplement - Juergen Fink
Funder: Wellcome Trust

Abstract: RESEARCH QUESTION ABSTRACT ONLY Increasing awareness and understanding of the promise and challenges of stem cell research is embedded in the Stem Cell Institute vision and summarised in one of five strategic goals: Communication and public engagement providing reliable information, useful resources, and dialogue opportunities for a range of audiences including schools, policy makers, patient groups, professional bodies and the media Accordingly SCI aims to promote and engage in public dialogue relating to stemcell science. The high level objectives of these public engagement activities are to contribute to: sustaining public support for stem cell research and science in general informing and influencing public policy encouraging uptake of careers in STEM subjects


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Cambridge Stem Cell Institute Four year PhD studentships - Stem Cell Biology.
Funder: Wellcome Trust

Abstract: Stem cell science is providing a stream of new knowledge about how our bodies are made and maintained. This research brings the promise that better understanding of stem cells will lead to future medical applications. Treatments may come through several routes. First, human stem cells grown in the laboratory can be used to produce experimental models of diseased tissues and to test therapeutic drugs. Second, some disorders, including forms of cancer, involve abnormal behaviour of stem cells. As we learn how to control stem cells it may become possible to correct these faults. Third, finding how to prevent a decline in numbers and activity of stem cells may help to maintain health during ageing. Finally, stem cells could be used to renew damaged tissues and replace missing cells in certain disorders. The Cambridge Stem Cell Institute is being formed to explore and define the properties of stem cells and establish their true medical potential. Leading research scientists, technology sp ecialists and doctors will work side by side to create a world-leading centre of excellence in stem cell biology and medicine. The Institute will also collaborate with bioindustry and will provide high level training for young researchers from around the world.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Wellcome Trust Technology Platform
Funder: Wellcome Trust

Abstract: We are requesting renewed strategic support for the Wellcome Trust Centre for Gene Regulation and Expression, (GRE) (http://gre.lifesci.dundee.ac.uk/), which was established in 2008 in the College of Life Sciences at the University of Dundee (http://www.lifesci.dundee.ac.uk/). Cells are the fundamental units of all life on earth and our research aims to characterise the basic molecular mechanisms and regulatory events that allow cells to grow, divide and interact with their environment. Recent t echnological advances in mass spectrometry, microscopy and high performance computing provide exciting new opportunities to study cells and their molecular interactions in unprecedented detail. The GRE Centre provides a highly interactive and multidisciplinary environment where the independent research groups focus on the quantitative analysis of genes and chromosomes in both human cells and other model organisms This application seeks funding to support the important activities within the Cent re that promote interactions between the groups and assist training of basic and clinical young researchers. We also seek funding for support staff and equipment in the core facilities we have established for proteomics, microscopy and high performance computing, which underpin projects within the GRE Centre and add maximum value to many other research groups throughout the College of Life Sciences.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Transcriptional Control of Stem Cell Fate.
Funder: Wellcome Trust

Abstract: Embryonic stem (ES) cells hold enormous promise for personalised medicine and drug discovery since they can be maintained indefinitely and are pluripotent; that is they have the potential to form any adult cell type. While pluripotency makes ES cells potentially very useful, it also presents a problem: how do you get them to make the cell type you want, and not one you don't? Differentiation of pluripotent cells is exquisitely organised during normal embryogenesis, but controlling differentiatio n of stem cells in culture presents a major challenge. In previous work we have shown that the ability to precisely control expression levels of key genes is crucial for the initial steps in ES cell differentiation. We will now investigate precisely how this gene expression control is carried out, how a seemingly uniform group of cells manages to differentiate into a wide array of different cell types, and we will identify more genes important for these differentiation choices. By understanding how ES cells make different developmental decisions this work will bring the medical promise of stem cells closer to realisation.


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