NIHRDataInsights/HRCSData huggingface dataset:
Title: Regulation of cell size in multicellular organisms
Funder: Wellcome Trust

Abstract: The aim of this research is to better understand the function of genes responsible for cell growth. Cell growth can be divided into two aspects, i.e. cell division and increase in cell size. Although cell division has been extensively studied for decades, much less is known about the genes and mechanisms responsible for controlling cell size. We have previously identified genes in the fruit fly (Drosophila melanogaster) that affect cell size. The fruit fly serves as an excellent model to underst and cellular processes due to its simplicity, yet most of its genes are also present in man and most of the cellular processes are well conserved. We have previously identified that some of the genes acting on cell growth function independently of effects on cell division, implicating that there are specific growth genes. Many of these genes apparently increase the efficiency of protein synthesis. We wish to better understand how these genes affect cell growth by identifying all the molecular ta rgets affected by them. As cell growth control is dysfunctional in many disease states, such as cancer and diabetes, this study may help to identify novel therapeutic targets for these diseases in the future.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulation of myosin II filament assembly and stabilization, localization, and cortical anchoring .
Funder: Wellcome Trust

Abstract: Muscle contraction is powered by a filamentous motor called myosin that pulls on long cables that extend the length of the cell. Nonmuscle cells use a very similar system of motors and cables to drive their migration (including the migration of metastatic cancer cells), division, and several other processes. However, unlike muscle cells, nonmuscle cells frequently assemble and disassemble this network of motors and cables to control these diverse functions. My challenge is to determine the ho w, where, when, and for how long of the assembly of these essential motor filaments and how this impacts cellular behavior. I will begin by studying how this motor system is linked to the cell membrane to drive its ingression during division. I will look for what anchors the motor in place and what controls its localization. Next I will begin studying the lifetimes of myosin filaments to understand how this parameter is changed and whether this changes what the motor does. I will also search for other factors that cause the motor filaments to assemble or disassemble. Overall, I hope to obtain a better understanding of the mechanisms cells utilize to allow a single motor and cable system to produce multiple different outcomes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Mechanisms of Muskelin/RanBP9/CTLH complex.
Funder: Wellcome Trust

Abstract: Just as the activities of our heart, brain and muscles need to be coordinated so that we can function in daily life, each cell needs to coordinate its activities. The cytoskeleton is a scaffold inside cells that enables them to change shape. To do this, the cytoskeleton itself must be able to change shape. My laboratory has been studying two proteins that are involved in how cells change shape. These proteins are linked to a larger complex, muskelin/RanBP9/CTLH complex, that we think acts to deg rade proteins linked to the cytoskeleton. Almost nothing is known about how this complex works in animal cells. Our goal is to understand how the complex is built and to identify proteins that it degrades. Hypoxia (lack of oxygen) is a major cause of tissue damage in stroke and cardiovascular disease. We have discovered that hypoxia changes the location of CTLH proteins in cells. We will work out how the location and organization of the complex, and its ability to degrade proteins, are changed b y hypoxia compared to normal conditions. This will give us and other researchers new knowledge of how cell activities change in diseased tissues. We will study these questions in cultured mammalian cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Enzyme regulation by allo-targeting: A strategic initiative for chemical biology and molecular therapeutics.
Funder: Wellcome Trust

Abstract: Most new drugs for human diseases target an important group of proteins called enzymes, by blocking a particular region (the active site ) in them. However, human cells require multiple enzymes to function normally, and the active sites of many of these are similar in structure. Therefore, drugs that block the active sites of enzymes are not sufficiently selective, leading to poor activity, and unwanted side-effects in patients. We propose here to develop new ways of making drugs that bl ock enzymes, not by targeting the active sites, but by disrupting interactions between enzymes and other proteins, which are necessary for the enzymes to work correctly. We call this approach allo-targeting because it targets outside the enzyme active site. To accomplish this aim, we will pioneer new methods to find drugs that disrupt interactions between proteins, using four enzymes important for disease therapy as path-finding examples. We will establish innovative new ways to test the ef fect on human cells of the drugs we discover in this way, to evaluate their potential for further development. Our work has the potential to transform the basic scientific research that helps us to understand human diseases, as well as the way new drugs are discovered and developed.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES;5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: Replacement of WTCHG Compute Cluster
Funder: Wellcome Trust

Abstract: RESEARCH QUESTION ABSTRACT ONLY New discoveries in genomics are transforming healthcare, as well as tracking the movements of populations throughout history, and elucidating the evolutionof life on Earth. Yet even the medically qualified are unsure what the impact of the genetic revolution might be, and many members of the public are hazy about the concepts of genes and genomes. As one of the leading laboratories in the UK exploring the links between genesand disease, the WTCHG wishes to engage a range of diverse audiences in interrogating the challenges of this new knowledge. We plan to undertake a focused programme of activities during the remainder of our core grant. The outcomes we intend to achieve are as follows: * A better understanding among our researchers of what members of our community expect from genomic approaches to medicine; * A better understanding in the community (including students in secondary schools and universities, patients and healthcare workers) of the possibilities and limits of the technology; * An increased appreciation that fundamental and applied research is exciting and fulfilling, especially among young people; and * Greater capacity to engage with diverse audiences among our early-career andsenior researchers. We will deliver our programme in partnership with local cultural organisations. The Oxford University Museum of Natural History welcomes over 650,000 visitors per year, and has a multi-award winning education team. The museums Director plans a new temporary gallery to showcase contemporary science in partnership with research departments. An independent trust, Science Oxford, provides science outreach and STEM ambassador training in Oxfordshire and neighbouring counties. We envisage a programme culminating in an exhibition lasting up to three months, with associated talks, debates, online resources (providing a legacy beyond the life of the physical exhibition), publications and school outreach visits. A possible topic might be The Genome Zoo: animal genomes, evolution and human health. To increase the ambition of our public engagement offer, WTCHG will recruit a full-time public engagement officer at Grade 7 on Oxford's salary scale. We seek to appoint someone with a science degree, further postgraduate study in either science or science communication, and experience in a public engagementrole. The successful applicant will implement a strategy including this programme of activities, in consultation with the Director and a subcommittee of senior PIs. He/she will ensure that the Centre participates in public engagement initiatives organised at departmental, institutional, local and national levels; develop partnerships; deploy digital media in support of public programmes; seek further funding to support specific projects; and implement a monitoring and evaluation strategy.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: The Consumption of Medical Services in Paris, c. 1650-c. 1750.
Funder: Wellcome Trust

Abstract: Was there a European revolution in the consumption of medical services in the early modern period? Mortimer has argued that one occurred in England but what happened in continental Europe? In order to answer to this question, I will study payments to healing practitioners in Paris between c.1650 and c.1750. Using debts recorded in a variety of different sources, my project will answer a number of questions about the changing structure and scale of medicine during this period, notably: Who supp lied commercial medical care in Paris, what services did healers offer and how did these changed How much did they expect to be paid for their work? To what extent could they extract payments from their patients and clients - children s tutors or the deceased s heirs? And how did medical provision change over time? By addressing these issues over the period in which Paris became a leading centre for medical and surgical knowledge and training, my project will give a unique insight into the makin g of the modern medical market and how it gave grounds to modern medical economic practices. In addition, it will provide a new methodology to study the early-modern medical market to other continental cities.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE
Title: Sequencing heterogeneous stock progenitor mouse strain genomes.
Funder: Wellcome Trust

Abstract: Our key aim is to explore the relationship between genetic and phenotypic variation. We will do this by completing the genomic sequence of seven inbred laboratory mouse strains by combining the sequence of large fragment DNA libraries with those of short fragment DNA libraries, which have already been generated as part of an MRC funded project. This will create a complete picture of the genomes of these mouse strains which are the progenitors of a large population (2,000) of mice for which we ha ve a rich set of phenotypes, including models of asthma, type 2 diabetes, anxiety and obesity. By combining sequence and phenotypic data we will determine whether sequence variants are likely to be contributing to disease susceptibility and variation in the phenotypes. We will also generate assemblies for 10 other mouse strains creating an unprecedented resource for comparative analysis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating the molecular mechanisms of homologous recombination at DNA double-strand breaks and perturbed replication forks.
Funder: Wellcome Trust

Abstract: The replication and maintenance of DNA is crucial to all living organisms, and depends on the coordinated action of many different protein machines. One of the many challenges for these machines is to overcome barriers in the DNA that block replication. Such barriers can result in the local disassembly of the replication machinery, which is believed to cause the recruitment of proteins whose actions can restart replication. These same proteins also repair broken DNA molecules through a process c alled recombination. However, recombination can cause undesirable rearrangements of the DNA, which can result in disease and death. Its use at sites of perturbed replication and broken DNA therefore has to be carefully controlled. Using a wide range of cutting-edge molecular biology techniques we aim to elucidate the mechanisms that promote and control recombination at sites of replication blockade and broken DNA. In particular we will make use of yeast strains in which we can induce replication blockage and DNA breakage at specific sites, and then follow how recombination proteins act at these sites using both physical assays and microscopic observation of fluorescently tagged proteins. Biochemical experiments will also be used to determine the precise mode of action of key proteins.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Securing the legacy of British surgical history: the pre 1800 print collections at The Royal College of Surgeons of England
Funder: Wellcome Trust

Abstract: 1. To improve access to, and increase use of, the printed collections by researchers in the history of medicine and science by cataloguing them online. We will provide c. 5086 bibliographic entries (1936 for the pre-1700 collection; c. 3150 for the 18th century); the records will also become available via Copac National, Academic, and Specialist Library Catalogue (Copac). These collections particularly illuminate the work and collections of John Hunter (1728-1793), his contemporaries and predecessors. We will document marginalia and evidence of provenance and ownership. It is likely that up to 12% of the holdings will be unique. 2. To help improve collection management and preservation of the Library's historical collections ensuring their long term survival. This project will achieve near complete cataloguing of the College Library's unique collections providing a knowledge map at collection level which will lay the foundation to inform a sustainable long term collection management strategy by providing detailed bibliographic data. The lack of online records for these early collections hampers our efforts in this area. 3. To extend existing collaboration across library, archive and museum domains within the College to further our aim of encouraging public engagement with the history of surgery. This project will enable us to carry forward our aim of uniting 'virtually' items scattered across the all the collections and enriching the experience and understanding of our users. The College archives hold related materials already catalogued online; the planned provision of federated searching across catalogues will create new synergies between the collections.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Immune cell signal integration in vivo.
Funder: Wellcome Trust

Abstract: We will use Drosophila embryonic hemocytes as a model to study cell migration and chemotaxis in vivo. We will initially investigate the dynamic interplay between microtubules and actin in migratory cells as well as further investigating the role of microtubules during contact inhibition and in the maintanence of polarity in hemocytes. In addition to elucidating their cytoskeletal regulation we will explore what external cues direct hemocyte migrations and how their contact inhibitory behaviour is regulated. To this end we will carry out a genome wide-RNAi screen allowing us to identify novel genes required for normal hemocyte dispersal during development as well as their rapid chemotaxis towards epithelial wounds. In addition we will carry out a microarray approach to probe the transcriptome of discrete populations of hemocytes at different developmental timepoints in order to understand the process of hemocyte maturation and specification during development. Finally we also plan t o continue our initial studies using Drosophila embryos as a model system for following bacterial infection in real time. We will test the in vivo function of genes previously identified in RNAi screens in vitro as being important for the recognition, engulfment and degradation of bacteria by S2 cells in culture.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Drosophila embryonic macrophages as a model system for studying migration and bacterial infection in real time.
Funder: Wellcome Trust

Abstract: The movement of different types of cells within the body is crucial to such processes as embryonic development, immunity and wound healing. In the body, migratory cells are exposed to a battery of signals from different sources. The cells have to integrate these signals and react to them accordingly. Outside a living body it is impossible to precisely duplicate the huge variety of chemical, physical and electrical messages that living cells recieve within one. Cells therefore often behave ve ry differently once they have been taken out of their natural environment and cultured in a dish. The experiments described here are designed to investigate how cells move in their natural environment. To answer this question I will study a highly migratory cell type known as a hemocyte which is found within the embryo of the fruit fly. We have developed a technique that allows us to make movies of these cells migrating within a living embryo and using the powerful experimental genetics avail able in Drosophila we can now begin to understand how these cells achieve their migrations both during normal embryonic development as well as during an emergency situation such as wound healing or in the fight against bacterial infection.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Control of noise in gene expression.
Funder: Wellcome Trust

Abstract: For normal development and functioning of organisms, genes must be switched onin the correct place and at the correct time. It is also important that geneshave the potential to stay switched on, otherwise cells lose the ability to perform key functions. In contexts where genes are not switched on correctly, or where genes are not on for the correct period of time, loss of cell function results, which can lead to many devastating human diseases. To study how the switching on and off of genes is controlled, we use a state-of-the-art technique, to directly watch single genes in living cells. Using a microscope, we can observe cells and assess whether a specific gene ison or off. We measure the number and duration of on and off periods, how these change when cells are stimulated, and how these change over time as the cells divide and grow. This allows us to precisely address how genes respond according to the cell environment, and to understand how long term stability of gene beha viour can be guaranteed, all to suit the needs of the organism.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Combined genetic and biochemical approaches to uncover and characterize redundant factors involved in late stages of recombinational repair.
Funder: Wellcome Trust

Abstract: Maintaining the integrity of the genetic material (genome) is essential for preserving genetic information and genetic mistakes (mutations) are associated with aging, hereditary diseases and cancer. In each of our ~100,000,0000,000,000 cells the genome is challenged by genotoxic agents that include UV and ionizing irradiation, reactive metabolites and environmental toxins. DNA double strand (DSB) breakage is the most deleterious lesion that also occurs during a normal cell division. DSBs can be fixed by a mechanism called recombinational repair without loosing genetic information. GEN-1 is a very recently discovered enzyme required for cutting cruciform DNA repair intermediate structures first postulated in 1964. We showed that GEN-1 is indeed required for DSB repair and that GEN-1 is required to confer signals instructing damaged cells to either transiently halt cell division in order to allow for time to repair, or to trigger cellular suicide if cells are beyond repair. We want to u se the C. elegans nematode model system combined with experimentation of a uniquely manipulatable vertebrate cell line to better understand how GEN-1 works. We hope to determine how GEN-1 acts as a signalling molecule and how, and with which other novel proteins it functions in DNA repair.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Proteomics at the Wellcome Trust Centre for Cell Biology.
Funder: Wellcome Trust

Abstract: Human health depends critically on the interactions between the thousands of different proteins in the cell. Our goal is to understand how complex networks of proteins control key cellular activities, such as cell division, cell growth, chromosome segregation and gene regulation. This requires that we identify, characterize and quantify the proteins specific to each process. Critically, in order to understand how collections of proteins control different processes, we need to decipher the wiring diagram of how proteins connect to each other and how these connections change under different conditions. We have developed a method that provides this information by permanently linking proteins via a chemical cross-linking reaction before analysis; these chemical cross-links stabilize protein interactions and thereby facilitate the deconstruction of protein networks. This method requires the use of a sophisticated instrument - called a mass spectrometer - to accurately identify proteins ba sed on their mass. We seek support for a next generation of mass spectrometer that will enable a 10-fold increase in sensitivity, which will be sufficient to map protein networks at an unprecedented level of detail. This instrumentation will reveal the inner working of complex cellular processes and how these networks change in human disease.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Examination of non-clinical inter-hospital critical care transfers: trends, causes and solutions .
Funder: Wellcome Trust

Abstract: Transferring a critically ill patient to another hospital is not without risk. They may deteriorate suddenly in an ambulance, where it is difficult to deliver care. Moving patients may be essential to access specialist treatment. However, at least 1500 transfers take place annually because there are no intensive care beds available locally. This is known as a non-clinical transfer (NCT). It is thought that NCT patients require longer in intensive care, which is costly for the NHS. However, there is still uncertainty about whether the process has other detrimental effects. Data collected by the Intensive Care National Audit and Research Centre will be used to examine the impact of NCTs, comparing patients who are transferred with those who are not. There is also variation in NCT rates nationally: in 2007, some hospitals transferred no patients, whilst others transferred 1 in 11. Interviews will be carried out with staff at hospitals with high NCT rates, to explore the reasons b ehind this. This study will make recommendations for policy and practice to reduce NCT rates. It is also important to establish the effect of transfers, because proposed hospital reforms may lead to more critically ill patients being transferred in the future.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE