NIHRDataInsights/HRCSData huggingface dataset:
Title: Generation, optimisation, validation and implementation of bacterial whole-cell biosensors for the detection of novel antibiotics
Funder: Wellcome Trust

Abstract: Antibiotics remain our primary means of treating bacterial infection. Unfortunately, these agents are increasingly being rendered ineffective by theemergence of antibiotic resistance, and the problem is compounded by the dearth of new antibiotics being discovered. Given the failure of rational/synthetic approaches to antibacterial discovery, drug developers are beginning to revisit the screening of natural products from microorganisms in an attempt to identify new antibiotics. This project will address some of the major deficiencies associated with current natural product screening methodologies, particularly the failure to detect antibiotics at low concentrations or in complex mixtures. This will be achieved through generation of bacterial whole-cell biosensors that produce a quantifiable output when exposed to inhibitors of a target pathway. The O'Neill laboratory has recently created first generation biosensors for detection of inhibitors of the peptidoglycan biosynthesis pathway. This project will seek to optimize the sensitivity of these biosensors using directed evolution and synthetic biology circuits, and will generate, validate and optimize biosensors for other target pathways in the bacterial cell (e.g. protein synthesis). Once established, these biosensors will be used for high-sensitivity screening of actinomycetes and other natural product producers to identify novel antibacterial drug candidates.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Using Cholera toxin B-chain as a system for the targeted delivery of proteins to motor neurons
Funder: Wellcome Trust

Abstract: The aims of the project are to design a method for the reversible binding of antibody-like proteins to Cholera Toxin B subunit (CTB) to facilitate their trafficking into cells. Initially, a screen against CTB will be carried out toidentify suitable Adhirons. These will be conjugated to a range of different proteins, before being combined with CTB, and administered to assess its ability to deliver the complex into motor neurons in vivo. There is currently no method to deliver antibody-like molecules into motor neurons selectively. Sublingual injection of CTB allows this group of neurons to be targeted specifically. This project therefore focuses on the design of an enabling technology to permit delivery of proteins into specific cell typesto address questions in neurobiology. By combining techniques from molecular biology and chemistry to generate the binding complex, and assessing the effect of these complexes on the nervous system in vivo, this project will provide an interdisciplinary approach to understanding neuronal function at the molecular level. Therefore, this project addresses one of the Wellcome Trusts five major research challenges, i.e., understanding the brain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating the Bax Interactome during Apoptotic Initiation
Funder: Wellcome Trust

Abstract: Apoptosis is a form of programmed cell death, the avoidance of which is a hallmark of all forms of cancer. The ability to reactivate apoptosis in tumourcells therefore constitutes a rational strategy for the development of effective cancer treatments. Apoptosis is predominantly initiated in cells viathe intrinsic pathway, which is triggered by various cellular stresses and culminates in cell death following cleavage of many cellular components. This pathway is modulated by the Bcl-2 protein family, whose pro- and anti-apoptotic members react to intracellular signals and interact to determine cellular fate. If pro-apoptotic signals predominate, a Bcl-2 family member called Bax moves from the cytosol to accumulate at the mitochondria, where it causes the mitochondrial membrane to permeabilise, releasing cytotoxic molecules into the cytosol. This constitutes the point of no return for the triggering of cell death. This project will identify the various protein partners that bind to Bax during its transformative journey from quiescent cytosolic molecule to cellular executioner at the mitochondrial membrane. It will aim to characterise the binding interactions between Bax and its partners, with the goal of elucidating mechanisms of Bax activation that can be used to inform the development of novel cancer therapies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Developing novel technologies for the investigation of ion channels and pumps
Funder: Wellcome Trust

Abstract: Transient receptor potential melastatin-2 (TRPM2) channel has been associated with a number of severe diseases, including diabetes and oxidative-stress related pathologies. Since it has been found that TRPM2 deletion protected mice from developing diet-induced obesity and insulin resistance it provides apromising drug target for diabetes. This projects aims to test a number of potentially targeting compounds for their inhibiting properties. This will go along with biophysical characterisation of the channel. In pancreatic Beta-cells TRPM2 is located in the cell membrane and the lysosome. In particular we are interested to see whether the lysosomal channel is able to release toxic, free zinc from the lysosomes into the cell. The problem with testing ligands is, that it is not possible to distinguish between direct and indirect effectors using whole cell patch clamping. Furthermore it is difficult to perform patch-clamping on isolated lysosomes. This project aims to develop novel solid-supported membrane systems as tools for biophysical characterisation of eukaryotic membrane proteins, in particular a double membrane system using TRPM2 as a model system. These systems could serve as a general platform to investigate membrane proteins and provide a model for double membrane systems such as the synaptic cleft.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural, biophysical and functional characterisation of the adhesion G-protein-coupled receptor Latrophilin and its binding partners
Funder: Wellcome Trust

Abstract: The Uncoordinated 5 (UNC5) receptor is emerging as a central node in a cell-surface signalling network controlling development of complex branched cell systems, such as those of the nervous and vascular systems. It is also becoming increasingly apparent that dysregulation of UNC5 and its interaction partners contributes to cancer progression. Whereas many of the branches of this signalling network are well characterised with respect to functional and molecular biological detail, the fibronectin leucine-rich transmembrane protein (FLRT), latrophilin (LPHN) and teneurin 2 (TEN2) branch remains relatively unexplored.This project aims to use a mixture of crystallographic, biophysical and functional characterisation to elucidate the molecular mechanisms underlying this pathway. The main aims of this project are: Produce crystal structures of both LPHN alone and in complex with its interaction partners, FLRT and UNC5. Structurally and biophysically characterise TEN2, and its complex with LPHN. Functionally characterise the FLRT-LPHN-TEN2 branch of the UNC5 signalling network, using existing collaborations with european groups that specialise instudying receptors such as these in a variety of in vivo and ex vivo assays. Use computational approaches to produce integrated models of receptors in complex lipid bilayers. Such models will be based on experimental structural and biophysical data.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: British Autozygosity Population Gene Function Study.
Funder: Wellcome Trust

Abstract: Parental relatedness (e.g. cousin marriage) is common in certain UK ethnic groups including the health disadvantaged British-Bangladeshi and British-Pakistani communities. Recent studies indicate that outbred human genomes contain ~100 genuine complete loss of function (LoF) variants. Consanguineous (parental and/or historic) individuals carry genomic regions identical-by-descent (autozygous), thus rare frequency variants occur as homozygous genotypes. Our knowledge of human gene function an d genome annotation remains incomplete. Characterisation and deep-phenotyping of healthy adult individuals enriched for naturally occurring homozygous knockout alleles will provide invaluable knowledge of human biology. We propose a large-scale community based exome sequencing programme of consanguineous individuals (25,000) of whom a subset (3,000) with genotypes of interest will be later recalled. We will focus on East London populations whose recruitment and recall will be coordinated arou nd our Whitechapel site. We will recall sequenced individuals possessing autozygous variants of biomedical importance (predicted complete LoF, coding, and regulatory) for deep-phenotyping and experimental medicine studies. Our proposal complements existing rare disease sequencing programmes, national sequencing studies (UK10K, DDD), and other UK BioResources (Cambridge and NIHR BioResources, TwinsUK and UK BioBank). We will substantially engage East London communities and increase our existing p ublic engagement activities around genetics and genomics.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Modulating the activity of the Hedgehog pathway: structural biology approach
Funder: Wellcome Trust

Abstract: The Hedgehog pathway is a morphogen pathway essential for tissue patterning and embryonic development. The hedgehog ligand is processed in the secreting cell, undergoing autocatalytic cleavage and addition of cholesterol in the same reaction. The ligand is then palmitoylated by Hedgehog acyltransferase (Hhat) and secreted via Dispatched. On the receiving cell, the ligand interacts with the receptor Patched, which releases the downstream effector Smoothened, turning the pathway on. The Hedgehog pathway is misregulated in several cancers including the most common basal cell carcinoma and designing inhibitors mainly for Smoothened, has been of high interest. Interestingly, hedgehog agonists are also being tested for neuroregeneration as a treatment for Down syndrome and Parkinson's disease. The aims of the project include: i) Determining the mechanism of a Sonic hedgehog inhibitor and designing a novel more potent compound; ii) Design novel modulators of the pathway targeting the extracellular domain of Smoothened; iii) Characterise an alternative hedgehog target Hhat. To achieve these aims, we will use a combination of in silico methods like molecular dynamics and docking, and biochemical, biophysical and structural laboratory methods.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: 3D Multiscale Mechanical Modelling of Tissue Growth.
Funder: Wellcome Trust

Abstract: Growth, from embryo to healthy adult, is a series of perfectly coordinated events. Each part of the body grows to a certain size and shape, and stops. After the initial growth, our bodies constantly renew themselves, in a coordinated manner. Faults in coordination can cause many diseases, including cancer in the case of overgrowth of cells. If we understand how growth is regulated, we can use this knowledge to stop overgrowth causing cancer, and ensure correct tissue regeneration in severe damag e. Cells communicate in many ways to ensure this coordination. One method is sending chemical signals to each other; this has been researched over many years. There is another set of tissue properties that can guide this communication: the mechanical properties. I am focused on this less explored field. When doing experiments, it is complicated to separate the effects of chemical and mechanical communications. To help with this problem, I will generate computer models of growing tissues, and mul tiplying cells. This will help us understand what we see in the real experiments and help us uncover the underlying mechanisms and controls. In the long run, this research will help to improve healing processes, guide regenerative treatments, and cancer therapies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Defining the host protective antigens of the mouse whipworm, Trichuris muris: Pathway to vaccination.
Funder: Wellcome Trust

Abstract: Infection with gastrointestinal nematodes is a major cause of morbidity in humans and animals. The overall aim of this project is to identify and characterise the host protective antigens secreted by the mouse whipworm, Trichuris muris. Since T. muris is a direct homologue of the human whipworm, T. trichiura, it is anticipated that this work will have translational application, bringing us one step closer to a vaccine for this globally important parasite. We provide preliminary data that suggests that we have isolated a sub-fraction of T. muris secreted proteins that elicit a host protective response. The antigenic component will be further refined and we will carry out vaccination studies to determine whether it stimulates protective immunity in vivo. We aim to investigate the biological function, localisation and expression of candidate host protective proteins and finally we will produce recombinant variants of key antigens for the development of experimental subunit vaccines.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Global regulation of mRNA processing during early Drosophila development.
Funder: Wellcome Trust

Abstract: Significant advances have been made over the last few decades in understandingthe process of transcription and its regulation throughout development or in response to cellular stresses. However, a major gap in understanding now is how mRNA processing kinetics are globally coordinated with transcription to fulfil the mRNA needs of any given cell. Therefore, this proposal aims to determine how mRNA processing is integrated with developmental time during Drosophila embryogenesis. Specifically, we will generate RNA-seq data from single Drosophila embryos and produce mathematical models describing the kinetics of processing for each mRNA. We will use this data to test the hypothesis that promoter proximal pausing of RNA polymerase II increases the efficiency of mRNA processing in vivo, by manipulating polymerase pausing through transgenic and genome engineering approaches. We will also use the RNAseq data to identify candidate transcripts undergoing nuclear retention,and test the hypothesis that nuclear retention represents a mechanism that is important for synchronising gene expression over a field of cells. Overall, data from this proposal will be relevant to humans due to the conservation of the processes involved, and serve as a platform for understanding how misregulation of RNA processing leads to developmental abnormalities and diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Cellular dynamics following repeated antigenic challenge: the immune response to Trichuris muris
Funder: Wellcome Trust

Abstract: Infection by soil-transmitted parasitic helminths (STH) is a global problem for animals and man. Many experimental studies investigating mechanisms of immunity to gastrointestinal dwelling nematodes have shown that type 2 cellular immune responses are responsible for the induction of protective immunity. The great majority of these laboratory experiments, however, are carried out following a single antigenic challenge via a single high dose infection. In contrast, within endemic countries, individuals are repeatedly challenged by low dose infections resulting in worm burden and chronic infection. Host protective immunity does build up, but slowly and is rarely complete. The cellular mechanisms underlying both resistance and immunoregulation generated under these conditions remain unknown. We will use the well-defined laboratory model system of STH (whipworm, Trichuris muris) and mimic a more natural nematode challenge whereby mice willbe infected repeatedly by low dose until partially resistant. The cellular mechanisms during repeated low dose infection will be explored and the roles of the innate, adaptive and regulatory responses will be investigated. Additionally, the effect that repeated T.muris infection has on the immune response to additional antigenic challenge will be determined.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Exploring the interplay between TRC40 and BAG6 in protein quality control.
Funder: Wellcome Trust

Abstract: TRC40 is a cytoplasmic ATPase that plays a central role in the post-translational delivery of tail-anchored membrane (TA) proteins to the endoplasmic reticulum. TA proteins first bind SGTA and the BAG6 complex, and these upstream components act to chaperone these substrates prior to loading them onto TRC40. BAG6 and SGTA also play an important role in the cytosolic quality control of aberrant and misfolded precursor proteins by regulating their ubiquitination and proteasomal degradation. Strikingly, GET3, the yeast homologue of TRC40, acts as an ATP-independent quality control factor that canbe switched to this activity from its ER delivery role in response to oxidative stress. The principal aim of this project is to establish whether mammalian TRC40 can also act as a molecular chaperone/quality control component, and is not simplyan ER delivery factor as previously assumed? Key objectives are to:1/ Generate defined TRC40 mutants and establish their effect on protein quality control 2/ Establish the role of BAG6 and SGTA in TRC40 mediated quality control 3/ Address the role of oxidative stress in regulating TRC40 function 4/ Define the contribution of TRC40 to protein aggregation events implicated in disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Chimeric Organisms and the Ethics of Humanization .
Funder: Wellcome Trust

Abstract: The funds requested will be used to support qualitative social sciences research into the ethical and legal principles that are emerging around research with chimeric organisms in the United States. These activities will feed into a larger comparative project on how nation-specific legal-constitutional regimes may be implicated in redefining the normative standards of the category human. Specific research activities will include interviewing members of Embryonic Stem Cell Research Oversight Comm ittees at Harvard University and the University of Wisconsin-Madison, as well as visits to stem cell laboratories at both these universities. During this time I will be based at Harvard University in the Program on Science, Technology and Society at the John F. Kennedy School of Government. In order to undertake the empirical research it will be necessary to spend approximately 4 months in the United States where I will a) gather collect of documents (e.g. policy and ethical guidelines, repo rts from advisory bodies, media coverage of scientific practice, biomedical journal articles); b) conduct semi-structured interviews with scientists and regulators; c) visit laboratories and institutional settings to observe the conduct and deliberation of those involved in scientific and regulatory practice.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: How does natural and anthropogenic disturbance change short- and long-term human population growth?.
Funder: Wellcome Trust

Abstract: Earth is not static. Civilisation is made by populations, both of which advance by responding to events that disturb the status quo. These disturbances are often short, but leave dynamic signatures (transients) that persist far into the future. In Europe, and beyond, the second world war left millions dead but those that survived produced a baby-booming generation that are now of an age where their increased relative abundance poses financial, social and moral questions for population health. Th e disturbances leave a quantifiable imprint, but we have no large scale understanding of how the transients vary. This New Investigator award will provide this on national, sub-national and city scales. The demographic impact of decisions made in particular countries (e.g., labour control in Iran) can be compared against informed baselines in relevant geographic, social and environmental contexts. Through collaboration with social scientists, the work has the potential to refine policy recommend ations of how we can improve population health through evidence-based understanding of how disturbances alter our demographic destiny.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: GENERIC HEALTH RELEVANCE
Title: Sustainable Healthy Urban Environments (SHUE) project
Funder: Wellcome Trust

Abstract: The environments and governance of cities have an important role in influencing the exposures and health-related behaviours of their populations. Cities also have a demand for resources beyond current limits of sustainability. The changes needed to help reduce these local and global environmental impacts offer opportunities for improving population health by reducing current unhealthy exposures and behaviours which also contribute to patterns of unsustainable living. However, as yet there is only patchy empirical evidence on the degree to which city characteristics are associated with variations in health-related exposures, behaviours and outcomes as well as greenhouse gas (GHG) emissions. This project will build up a detailed database of a globally-distributed selected sample of cities and their populations with the aim of identifying the inter-relationship between city characteristics, their use of energy and other resources, and health-related behaviours and exposures. From comparative analyses combined with health modelling, we will assess the potential impact on health of realistic options for more sustainable strategies in such areas as transport policy and infrastructure, aiming to identify examples and principles to promote health and sustainability that can be more widely applied. The resulting database will be an open access resource for the research community and can be expanded over time.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: GENERIC HEALTH RELEVANCE