NIHRDataInsights/HRCSData huggingface dataset:
Title: Transcriptional Control of Endothelial Tip Cell Behaviour and New Blood Vessel Sprouting.
Funder: Wellcome Trust

Abstract: Diseases such as cancer, stroke, heart disease and arthritis involve the dysregulation of new blood vessel growth (angiogenesis) and are a major cause of illness and death. Consequently, understanding how angiogenesis is regulated is essential for the development of therapeutics to treat these disorders. During angiogenesis, vascular cells need to acquire very specialised tip cell behaviour, which is essential for coordinating the movement of vascular cells during new blood vessel sprouting. A cquisition of tip cell behaviour involves the controlled expression of certain genes in these cells. However, the mechanisms regulating tip cell gene expression are unclear. My research will: 1) Identify and determine the function of proteins that bind DNA (transcription factors) to turn on gene expression specifically in tip cells. In addition, the function of genes whose expression is regulated by these transcription factors will also be investigated. 2) Define DNA sequences bound by tip cell-specific transcription factors, which are responsible for promoting tip cell gene expression. This information will be used to make zebrafish genetic tools, which will allow the identification of previously unknown signalling pathways that turn tip cell gene expression on or off during angiogenesis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural role of BET bromodomains in transcription.
Funder: Wellcome Trust

Abstract: Bromodomains are proteins that can recognize chemical modifications found on proteins, and bind to them, thus translating chemical signals into assemblies of higher order organizations resulting in the build-up of large architectures. Such protein assemblies are used by living cells to perform complicated functions, such as the duplication of the cell s genetic material. In disease, properties of proteins are perturbed resulting in the disruption of molecular assemblies and their natural functio n. Viruses also perturb these regulatory complexes in ways that allow them to propagate and survive. Understanding the mechanics of interactions between proteins helps us demystify their deregulation in disease thus allowing for the development of therapies. This project aims to address the role of a subset of bromodomain proteins into the formation of larger complexes, which are responsible for the duplication of the cell s genetic material, by identifying their specific recognition partners an d exploring their binding properties, seeking to generate three dimensional crystal-clear images of their interactions by utilizing biophysical techniques of analysis. In addition, it aims to elucidate how and to what extent these interactions are perturbed by viruses or cancer, where bromodomains are altered and become fused to oncogenic elements resulting in disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: 'Better by Degrees': Recovery from Illness in Early Modern England, c.1580-1720.
Funder: Wellcome Trust

Abstract: The historiography of early modern medicine has tended to paint a negative picture of health at this time, implying that death was the most common outcome of illness. By focusing on the subject of recovery, this project will provide a more balanced interpretation. It takes the perspectives of three groups: medical practitioners, patients, and patients families. There are four aims Firstly, to reveal medical perceptions of recovery, asking how people understood and defined the processes by whic h health was restored. Secondly, I will ask what types of care were provided to recovering patients. Thirdly, the project examines the experience of the patient. What emotions did people express when they were getting better? Did they regard recovery as a sign of God s love and approval? Fourthly, I will unveil the experience of the patient s family and friends- how did they respond emotionally to the recovery of a loved one? Were celebrations arranged to mark the occasion? These questions will shed light on broader historical issues, such as concepts of the body, the relationship between religion and medicine, and experiences of emotions. A wide range of sources will be used, including personal documents, medical texts, legal documents, and popular and religious literature.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Textual Initiation in Tibetan medical education.
Funder: Wellcome Trust

Abstract: This research will examine the Tibetan medical education system as a whole and the teaching methods with a focus on textual initiation - one of three major traditional teaching methods. The other two methods are so-called 'didactic learning' and 'empowerment'. Textual initiation means the oral/aural transmission of original medical manuscripts, passed down by the senior custodians and holders of this historic tradition. To date, despite the significance of this teaching method in the overall education of Tibetan medicine, there is no proper documentation of the historical sources, lineages and recent practitioners who have taken part in the transmission of this tradition through textual initiation even in Tibetan. There is also no scholarly assessment of why this is an essential part of the Tibetan medical education system. Given that the few significant traditional holders of textual initiation through oral transmission live in remote villages and are very advanced in age, it i s vital to conduct research to identify these lineages and document the practices associated with them before they die out. This work will also inform policymaking at the university / curricular level.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: The Emergence of Systems Biology .
Funder: Wellcome Trust

Abstract: Over the last forty years biological and medical sciences have undergone a revolution, as new techniques of analysis and information handling have produced masses of data on the key molecules in living cells. Even though these developments are recent, historians can use their skills and experience to show how the biological revolution came about. We have chosen to analyse a very recent discipline, systems biology, which draws on the masses of new data to make computer models of living cells. Using documents and interviews we will show how the new field developed, how it drew on other subjects, how it differed between places, and how international research programmes were created. We will analyse the claims made for the new discipline, including the use of philosophers and social scientists. Our study will include skeptics as well as enthusiasts, and we will try hard to disentangle results from rhetoric. This pioneering venture in the critical history of the present will help equ ip scientists, policy makers and the general reader to see the biological revolution as part of wider recent history, influenced by the differing institutional configurations within and across nations, and shaped by rivalries and debates, as well as laboratory results.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES);8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural basis for stable kinetochore-microtubule attachments and timely onset of anaphase by the Ska Complex.
Funder: Wellcome Trust

Abstract: In human body millions of cells undergo division called mitosis every minute. Mitosis ensures that the daughter cells receive accurate genetic information from the mother cell. This is essential as aberrant genetic transfer leading to a state called aneuploidy (abnormal chromosomal content of a cell) is often linked to cancer, uncontrolled cell division. Hence, understanding the mechanisms that ensure the accurate cell division is basic in fighting human health related disorders. A large number of proteins work in conjunction during various stages of mitosis in ensuring the accurate cell division. Among the important stages, assembly of kinetochore (a large proteineaous structure) on a specified region of the chromosomes and its attachment to microtubules (a filamentous protein structure) are very crucial, as aberrant attachment might lead to daughter cells having inappropriate number of chromosomes. The proposed research aims to understand how various kinetochore-associated proteins i nteract with each other to establish correct kinetochore-Microtubule attachments and achieve accurate chromosome segregation by structurally characterizing the protein interactions mainly using X- ray crystallography methods in combination with biochemistry and molecular biology.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular mechanisms of filopodia formation.
Funder: Wellcome Trust

Abstract: Filopodia are made up of actin filaments and appear to form in response to the clustering of actin regulatory proteins on the cell membrane of motile cells. It is unknown what makes the tip complex start to form or how it gives rise to distinctive actin morphology. I discovered a way recreating filopodia-like structures using artificial membranes and cell extracts. I will exploit this novel system to elucidate how filopodia are formed by (1) determining the contributions of actin regulatory pr oteins that I think might be important for deciding where a filopodium is going to form and how it is elongated. It is easier to do these studies in a test tube as the process is slower and I can add and remove components and watch the process as it happens; (2) finding where actin regulatory proteins are located within the tip complex to understand how it functions; (3) study how filopodia made naturally in embryos are formed so that we may better understand how cells determine when and where f ilopodia are made, find out whether all filopodia are the same, and elucidate the roles of filopodia in development and disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The assembly mechanism of higher order protein assemblies.
Funder: Wellcome Trust

Abstract: Many, if not most critical cellular functions are carried out by sophisticated assemblies of proteins or protein complexes and there is virtually no life without them. Some complexes seem to assemble just fine but there is growing evidence that this process is controlled and catalysed in cells. So far it has been very difficult to address this question, as the required technology is not readily available. But recent developments in the field of mass spectrometry and proteomics make the developme nt of a technique to study the assembly pathway of protein complexes feasible. The aim of this research proposal is to find out if such a general mechanism, basically a scaffold for complex assembly, does exist in cells. In order to achieve this goal, a technology platform capable of generally studying this fundamental biological process will be developed. The technology will be first implemented and subsequently tested studying a highly important protein complex, the anaphase promoting complex (APC), as an example. The APC is highly suitable as a proof of principle, as its cellular abundance is comparable to many other complexes and as it is a major regulator of the cell cycle, where aberrant behaviour can cause cancer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: High resolution genome-wide analysis of small RNA mediated translational regulation.
Funder: Wellcome Trust

Abstract: The central dogma of molecular biology articulated by Francis Crick (1958) describes the flow of genetic information between three biopolymers: DNA, RNA and protein. The fundamental transfers of biological information are: DNA replication (DNA copied into DNA, the hereditary carrier of genetic information); transcription (DNA copied into messenger-RNA); and translation (protein synthesis using the information encoded in messenger-RNA). All life forms ranging from bacteria to human are dependent on these processes. More recently, scientists have come to appreciate the importance of a new layer of information carried by RNAs that do not code for proteins. One important class of these RNAs comprises the microRNAs which are found in organisms ranging from the unicellular alga Chlamydomonas to human, and are involved in numerous gene-regulatory pathways. MicroRNAs are now an extremely important tool for biomedical research. However, although microRNAs are known to regulate translation, the mechanisms involved remain unclear. I will address this problem using high-precision and high-resolution genomic techniques. By comparing organisms as diverse as Chlamydomonas and human, I will obtain powerful evolutionary comparative information on microRNA-pathways. The results will provide crucial new insights into microRNA-based gene regulation, and provide important groundwork for developing new RNA-mediated tools for biomedical research.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Interrogating the roles of miRNAs in entering and exiting ground state pluripotency in embryonic stem cells.
Funder: Wellcome Trust

Abstract: Embryonic stem cells have the unique capacity to become all cell types of the body, a process termed differentiation. Mature cells, such as skin and blood cells, can revert back to this versatile stem cell state in a process termed reprogramming. Understanding both of these processes is crucial in advancing cell-replacement therapy. This therapy relies on reprogramming patient cells to the stem cell state and subsequent differentiation of these cells to clinically relevant cell types for transpl antation. However, the fundamental details of differentiation and reprogramming are largely unknown and this presents significant challenges for effectively generating stem cells and differentiated cells that are suitable for clinical applications. Additionally, diseases such as cancer arise when cells lose control in maintaining their differentiated status. Thus, mastering the control systems in differentiation and reprogramming will afford new insights into cancer formation. This research will provide deep understanding into the molecular controls of differentiation and reprogramming. In particular, the regulation mediated by a class of small molecules, microRNAs, will be the focus. Knowledge gained from this work will not only lead to the provision of safer and effective cell-bases therapies for patients, but will also present new avenues for formulating drugs against cancer.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE
Title: The mechanism of mRNA transport and localised translation during axis specification and synaptic plasticity.
Funder: Wellcome Trust

Abstract: Cells have an elaborate intracellular transport system that moves their protein building blocks to where they are required. Transporting messenger RNA (mRNA), which contains copies of the information for translating genes to proteins, is an efficient way to deliver proteins to their cellular destination. Such mRNA localisation is common in most cells and types of animals, but less is known about how it is achieved than about many other equivalent cellular processes. It sets up the first spatial landmarks in eggs and allows rapid local decisions to be made at the periphery of neurons during learning. Furthermore, defective mRNA transport within neurons is implicated in neurodegenerative diseases. We have discovered a set of shared protein factors required for mRNA localisation and regulating local protein production in Drosophila and vertebrate oocytes and neurons. We propose to use oocytes to discover how these proteins function in transport and translation of gurken mRNA, which encode s an extracellular signaling protein that sets up polarity in the oocyte. We will apply these findings to the nervous system, where these processes are less well understood, by discovering new localised neuronal mRNAs and developing novel microscopy methods for studying their movement and translational regulation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: 'The Global Health Bioethics Network: a programme to carry out ethics research and build ethics capacity across the Wellcome Trust's Major Overseas Programmes.'
Funder: Wellcome Trust

Abstract: Enormous global inequalities exist in health measures such as mortality, quality of life and disease despite increasing levels of overall wealth. In recent years, partly because of initiatives like the Wellcome Trust s Major Overseas Programmes (MOPs), there has been an unprecedented increase in the amount of research carried out on global health. Global health research, often bringing together multiple partners from sites in developing and developed countries, presents a range of important ethi cal and social issues not previously found in combination. These include issues relating to the sharing of data and biological samples between developing and developed countries, and to the question of what is to count as valid consent in the context of research occurring in multiple developing country settings. Identifying and addressing these important issues is essential for successful and appropriate science and for the achievement of the goals set out in the Wellcome Trust s Strategic Plan. The MOPs do not currently have sufficient capacity in ethics and community engagement to effectively engage with these important problems Against this background, the aim of this proposal is to build ethics expertise and capacity across the MOPs by combining world-class research with a well-managed programme of networked, locally-driven capacity-building activities.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Identification of interaction partners and functions of the calcium binding protein CaBP7 during cytokinesis
Funder: Wellcome Trust

Abstract: Mitosis is an essential process whereby chromosomes are duplicated and segregated into two identical daughter cells. Failure to do so can result in aneuploidy (abnormal chromosome number). Mitosis can be divided into several steps including interphase, prophase, pro-metaphase, metaphase, anaphase, telophase and finally cytokinesis, whereby the cell is divided into two cells,maintaining the chromosome number from one generation to the next. Many proteins are involved in this highly complex process including calcium sensor proteins, such as calmodulin. However the exact mechanism of function of thesecalcium sensor proteins during mitosis is still unknown. Recent work has suggested that the small calcium binding protein CaBP7 plays a role in mitosis, more precisely in cytokinesis. Additionally, this protein has been shown to localize extensively to lysosomes during cytokinesis and this requires further investigation. This project will aim to identify key target proteins for CaBP7 during cytokinesis and to investigate the cellular role of CaBP7 and its partners in cytokinesis. Additionally, the potential for a role of lysosomal calcium release will be examined. Overall this will provide further insights into the molecular mechanisms underlying CaBP7 function and its regulatory role during cytokinesis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Profiling and characterising differential deubiquitylase activity during the cell cycle
Funder: Wellcome Trust

Abstract: A family of around eighty deubiquitylases (DUBs) can reverse the effects of ubiquitylation to stabilise proteins, or regulate their activity and localisation. Whilst phosphorylation, dephosphorylation and ubiquitylation play well-established roles in cell cycle progression, our understanding of the role for deubiquitylation is less developed. In a preliminary screen using immunoblotting for tagged ubiquitin activity probes we identified changes in the activity of specific DUBs between mitotic and interphase cell extracts, including USP7 which was highly active during interphase, but inactivated at mitosis. The key goals of this studentship are to: 1. Systematically profile changes in enzymatic activity for the family of DUBsduring key transitions of the cell cycle using pull-down of tagged ubiquitin activity probes coupled with mass spectrometry. 2. Elucidate the mechanism by which cell cycle-dependent DUB activity is regulated. For USP7, and other key cell cycle-regulated DUBs we identify, we will investigate cyclical changes in their phosphorylation status, cellular localisation, and protein interactions. 3. Provide mechanistic insight into the role of these DUBs during the cell cycle. We will establish whether appropriate USP7 regulation is crucial to the deubiquitylation of key substrates, or to normal cell cycle progression using expression of non-regulated mutants.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Embedding Biobanks as Tools for Genomic Medicine.
Funder: Wellcome Trust

Abstract: There are lots of scientific inventions that never make their way into the clinic. This is because we do not have good systems in place to allow research findings to be rapidly implemented to help patients. Experts believe that by 2020 we will know more about how our DNA affects our health than we do now. This information could help lots of patients, but it will be useless unless doctors know about it. The aim of this research is to improve this situation by working with the Oxford Radcliffe Bio bank (ORB). This biobank holds lots of samples and information that are used for many different research purposes, but it could also be used to decide what treatments to give people. If this happened then the results from research would go directly to the patients who needed this information. However to do this requires new ways of working and thinking. Lessons can be learnt by interviewing all the people involved in ORB as well as visiting other countries, like the USA and the Netherlands, wher e they are more advanced in translational research. These results could help other countries within Europe and elsewhere where they are also trying to solve these problems


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE