NIHRDataInsights/HRCSData huggingface dataset:
Title: Investigating the role of IPIP27 in cytokines.
Funder: Wellcome Trust

Abstract: Cytokinesis is the essential process by which eukaryotic cells physically separate and defects in this process may lead to cancer. OCRL, the phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2 -5 phosphatase that is mutated in Lowe Syndrome and Dent disease, plays a role in cytokinesis and hydrolyses PI(4,5)P2 for the final abscission stage of cytokinesis, although the molecular mechanisms remain to be defined. IPIP27 was recently identified as a novel OCRL binding partner, and exists as two paralogues in humans: IPIP27A and IPIP27B. IPIP27A binds several actin-associated proteins, including CD2AP, which is known to play a role in cytokinesis and Pacsin2, forwhich a role in cytokinesis has also recently been suggested. Preliminary datahas shown localisation of IPIP27A to the midbody of dividing cells and initialfunctional experiments indicated cell division defects upon RNAi interference of IPIP27A. IPIP27B did not localise to the midbody. Therefore it is hypothesised that IPIP27A is potentially a novel regulator of cytokinesis, by remodelling the actin cytoskeleton in early cytokinesis and possibly by linking OCRL to the actin machinery to drive abscission. The project aims to test these hypotheses. Key goals include confirming IPIP27A localisation in dividing cells, characterising its function, and defining the molecular mechanisms of its role in cytokinesis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: UK Biobank: Funding application for assays of blood biomarkers in all 500,000 participants.
Funder: Wellcome Trust

Abstract: The aim of this proposal is to perform a wide range of biochemical measurements (biomarkers) in stored samples collected at baseline from all 500,000 participants in order to enhance the value of the UK Biobank Resource for researchers. UK Biobank's Enhancements Working Group has been responsible for developing the present proposal for biomarker assessments following extensive consultation with relevant experts to identify biomarkers likely to be of most scientific relevance for studying a wide range of diseases. The biomarkers selected for assay have been chosen because they are established risk factors for disease, diagnostic measures, markers of exposure, or characterize phenotypes not otherwise well assessed (see Section 2.2). UK Biobank's International Scientific Advisory Board endorsed the strategy of analysing a standard set of assays in all of the participants. Some of the ways in which it would enhance the value of the Resource are outlined below.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: GENERIC HEALTH RELEVANCE
Title: Cell biological functions of Daam-1 and CIP4 family proteins and their contributions to morphogenesis.
Funder: Wellcome Trust

Abstract: Morphogenesis in the whole organism is, at the molecular level, carried out byeach cell remodelling its cytoskeleton and membrane. Understanding how signalling in embryos gives rise to specific cell movements requires elucidation of the regulatory machinery that controls actin dynamics. We will study two actin regulators, the CIP4 family of membrane adaptor proteins and Daam-1 formin. Both proteins are implicated in the formation of finger-like protrusions from cells, filopodia, which are ubiquitously present on cells undergoing morphogenesis. By measuring the order and hierarchy of CIP4 proteinand Daam-1 recruitment to filopodia in diverse morphogenetic contexts (using Drosophila and Xenopus model organisms) we will find out whether they are always used in the same way. This will start to answer whether all filopodia have the same underlying molecular basis. In one context, convergent extension of Xenopus mesoderm during gastrulation, we have preliminary data that although the proteins localize to filopodia this may not be their dominant function. Instead, they are implicated in endocytosis and we will ask


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The developmental basis of wing pattern diversity in Heliconius butterflies.
Funder: Wellcome Trust

Abstract: The main goal of this proposal is to understand how developmental networks evolve during an adaptive radiation. Some lineages evolve rapidly, while others are highly conserved, and we would like to understand how the developmental networks underlying rapidly radiating traits differ from those that evolve more slowly. Mimicry among butterfly species is a commonly cited example of adaptation, and Heliconius are now the best-understood example of mimicry at a molecular level. 1) Bioinformatic characterisation of a patterning locus. We will conduct bioinforcharacterisation of the BD patterning locus and develop hypotheses for the regulatory function of this locus 2) Description of the upstream patterning landscape. We will investigate candidate genes that regulate upstream patterning of the switch locus and test the extent to which this patterning network is conserved in outgroups to Heliconius. We will use RNA-seq to identify genes that are differentially 3) Developing tests of gene function in Heliconius. We will develop experimental methods for testing gene function in Heliconius such as CRISPR gene editing and apply these to the patterning networks.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The role of nuclear organisation in the Notch response.
Funder: Wellcome Trust

Abstract: The highly conserved Notch intercellular signalling pathway controls developmentally important genes, contributes to tissue homeostasis throughout life and is altered in many human diseases. As the transduction pathway impacts directly on gene expression through the DNA binding protein CSL, understanding the mechanisms that enable the rapid and correct selection of targets is important, as well as being a valuable paradigm for TF binding in general. Our current models, based on linear DNA accessibility, are insufficient to explain Notch/CSL mediated gene regulation. One possibility isthat the nuclear location of specific genes, within the overall 3D organization of the genome, contributes to their efficient regulation. This project will test the hypothesis that the organisation of the genome contributes to the rapid changes in gene expression that follow activation of Notch signalling. Key goals: 1. To determine whether Notch responsive genes are associated with nuclear pores pores before or after activation. 2. To ascertain the extent to which Notch responsive genes associate together in space within the nucleus. 3. To test the relevance of nuclear organization for Notch target gene responsiveness.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating the mechanism of the V-ATPase and development of labelling methodology for ligand binding identification.
Funder: Wellcome Trust

Abstract: Despite membrane proteins being essential for cellular growth and homeostasis they are often a poorly understood area of biology. The mechanistic understanding of membrane proteins may lead to novel therapeutics, but is hindered by the lack of detailed structure-function studies. A challenge in membrane protein therapeutic design is the difficulty in obtaining structural data of drug binding sites using crystallographic techniques. This project will investigate the mechanisms of activation and inhibition of membrane proteins using electron microscopy. Chemical tools such as caged ligands and tag transfer reagents will be used to allow temporal control of protein conformation and to enhance contrast in imaging, respectively. The projects key goals are; 1) Elucidate dynamic and mechanistic information on the rotary proton pump V-ATPase, which works in the ms time frame and is implicated in many disease states, yet relatively little is known about the mechanism of action.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Investigating mechano-transduction across bacterial protein networks.
Funder: Wellcome Trust

Abstract: A large number of biological processes mediate protein-protein interactions through ?-sheet augmentation or complementation (1). Some protein networks that are stabilised by these small surface area interactions and are also resistant to mechanical extension as part of their function. In this proposal,our key goals are to: 1. Identify the origin of mechanical strength in structurally distinct ?-strand addition interactions in two bacterial systems (TonB-dependent transport (TonB/BtuB) and type 1 adhesion pili (FimG and the donor strand of FimF)). We will compare the effects of conventional mutagenesis, to that of amine-to-ester chemical substitution to probe the relative importance of hydrophobic interactions and main-chain hydrogen bonding. Molecular dynamic (MD) simulations will be used to pinpoint bonds which are crucial for complex stability. 2. Understand the role of mechanical force in inside-out energy transduction of the TonB-dependent transport system. This will be done by recapitulating the proposed process of BtuB remodelling by TonB (2) using atomic force microscopy (AFM) on the membrane bound receptor (BtuB) and supporting this with MD simulations. As mechanically resistant interactions are involved in infection, immunity andcancer (3), a fundamental understanding of the origins of strength and stability will be essential for future drug development.


Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural and mechanistic insights into ligand binding in P2X7 receptors.
Funder: Wellcome Trust

Abstract: The human P2X7 receptor (hP2X7R) is a ligand-gated cationic channel which plays a key role in mediating a number of diverse physiological functions induced by extracellular ATP. Alteration in receptor expression and/or function is linked to pathologies including chronic pain, rheumatoid arthritis, neurodegenerative diseases and cancers, which has made the P2X7R anattractive therapeutic target to the pharmaceutical industry. A thorough understanding of the P2X7R structure-function relationship is therefore increasingly crucial to develop P2X7R ligands as therapeutics. This project aims to: 1. Produce models of the P2X7R from different species and use these models andligand docking to map ligand-receptor interactions. These models will then be used to identify a subset of residues within the hP2X7R which are key for ligand-receptor interactions. 2. Investigate the role of key residues identified from modelling and docking by combining site-directed mutagenesis and patch-clamp recording to gain insights into interactions of ATP and antagonist with the hP2X7R. 3. Determine the conformational changes in the hP2X7R between the closed and ATP-bound open states and antagonist-receptor interactions using electron microscopy. These studies will enable us to build a structural and mechanistic understanding of the hP2X7R to facilitate development of therapeutic compoundsand understanding of disease mechanisms.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The Secret Life of Proteins - Computational and Experimental Studies of Moonlighting Proteins.
Funder: Wellcome Trust

Abstract: The aim of the project is to further our understanding of protein moonlighting (multiple unrelatedfunctions of a single protein). During this project we will explore a number of questions that relate to the molecular mechanisms and properties that allow or enhance the moonlighting potential of a protein. the project will concentrate on computational approaches wit the aim of producing testable predictions, which we then hope to veryify with experimental studies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Design and synthesis of medium-ring compounds to target nucleotide binding sites
Funder: Wellcome Trust

Abstract: Hypothesis That compounds based on a medium ring scaffold incorporating a ribose mimic can be potent and selective inhibitors of nucleotide-dependent enzymes. Aims The aim of the project is to synthesise a library of compounds based on a 9-membered medium ring core and screen them for inhibition of the HSP70 protein family. The major points of variation for the library will be the 3-position ether (R1) and at the 7-position (R2). As shown by comparison with ATP and modelling within the active site of HSP70, the R1 substituents will primarily mimic the adenine portion of ATP while the R2 substituents will mimic the triphosphate region of a nucleotide.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE
Title: Modulation of the folding energy landscape of a nascent polypeptide by interactions with the ribosome surface.
Funder: Wellcome Trust

Abstract: He we propose identifying and developing a fast-folding protein domain as the new ribosome-nascent chain complex (RNC) system, and using a series of destabilising mutations to determine the effect of ribosome attachement on the foding eneregy landscape. Key goals in this project are the establishment of a suitable RNC system; development of NMR methodology for the study of surface interactions; and ultimately measurement of the effect ofribosomal attachment on the protein folding energy landscape.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Analysi of loss of function variants from the British Autozygosity Population Project
Funder: Wellcome Trust

Abstract: Many human genes have poorly characterized function, and human genome annotation remains incomplete. The field has made headway in identifYing loss of function (LoF) mutations that are responsible for many rare inherited diseases and we observe homozygous LoF mutations in some other genes in otherwise healthy adult individuals2,3. Consanguineous individuals, for example offspring of cousin marriages, have autozygous regions in which rare LoF mutations lead to full loss of function of the gene because they are homozygosed. The primary goal of this research project is to contribute to a study designed to identifY a human knockout resource using DNA sequences from up to 25,000 consanguineous individuals possessing autozygous variants, primarily from South Asian communities in the UK, and to study these individuals in depth with targeted phenotyping for selected variants of biomedical importance in order to understand the impact of homozygous knockouts in the human genome. Additionally, these studies wil1 allow us to characterise the population architecture of deleterious mutations in humans, provide a much fuller genetic characterisation of the relevant (understudied) populations, and contribute to the management of the genetic health of these populations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Group sequential designs for crossover trials
Funder: Wellcome Trust

Abstract: Group sequential designs have proven a significant advancement over the classical randomisedtwo-arm clinical trial. Meanwhile, crossover trials remainan important approach in the development of many drugs, particularly those forthe treatment of chronic diseases. It seems logical that group sequential approaches to crossover trials could provide a substantial saving in terms of theexpected sample size required; thus facilitating faster development of prospective drugs, at reduced cost. We here propose to develop such a methodology. This will require the creation of new optimal stopping boundaries, similar to those for group sequential designs, but specifically designed for crossover trials. Moreover, potential required re-randomisation in the trial, due to the possibility for dropping treatments on futility grounds, will necessitate the construction of algorithms for creating optimal treatment sequences. All created methods will be designed to be able to control both type-I and type II errors. Finally, extension to dose response interventions and multiple trial endpoint types will be sought.


Research activity codes: 5.1 PHARMACEUTICALS;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: The Regulation and Consequences of REST Expression During the Cell Cycle.
Funder: Wellcome Trust

Abstract: REST is a transcriptional repressor with a vast repertoire of context-dependent target genes, whose dysregulation is associated with neurodegenerative disease and cancer. REST controls expression of protein-coding mRNAs and regulatory non-coding RNAs, which may act in feedbackloops to determine protein expression. It is tightly controlled, e.g. by alternative splicing, nucleocytoplasmic shuttling and post-translational modifications, which regulate REST expression and function. Notably, during the cell cycle, REST is ubiquitylated and degraded at G2/M; we have shown thatrapid resynthesis of REST at mitotic exit is dependent on the deubiquitylase USP15. Importantly, to date, there has been no systematic analysis of REST regulation throughout the cell cycle, nor is it known which genes are obligatetargets for REST at mitotic exit. The REST repressor engages in cross talk with other transcriptional regulators, and our preliminary SILAC-based mass spectrometry experiments revealed an overlap between the REST-dependent proteome and NRF2-dependent genes. The key goals of this project are to: (i) delineate the periodicity of REST splicing, expression, post-translational modification and localisation throughout the cell cycle; (ii) explore the molecular mechanism and cell cycle-dependence of the interplay between REST and NRF2; (iii) profile REST-dependent transcript and protein level changes that occur at mitotic exit.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Modelling pathological wound healing
Funder: Wellcome Trust

Abstract: Wound healing is a complex process consisting of several overlapping stages mediated by a network of signalling molecules. Mathematical models have been extensively applied to this area of study, however theoretical investigations generally focus on a single stage of the process in isolation, and fail to incorporate the role of signalling molecules such as cytokines in mechanistic detail. Recent experimental studies have suggested that the timing of events such as cell proliferation play an important role in determining healing outcomes, but this hypothesis is yet to be studied using mathematical approaches. We aim to produce a more complete mathematical model of the overall wound healing process, using ordinary and partial differential equation approaches to describe the underlying molecular and biophysical mechanisms Model predictions will be compared to in vivo experimental findings, making use of quantitative measures of features of the repair process (such as epithelial proliferation rates) wherever possible. The models will be refined accordinglyand used to investigate the effect of delays in the onset of cell proliferation on healing outcomes


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Dissection of temporal information processing by the glucose-sensing network of Saccaromyces cerevisiae
Funder: Wellcome Trust

Abstract: Though microorganisms inhabit fluctuating environments, some events can have temporal correlations. For Saccharomyces cerevisiae, such events can be increases in glucose, followed by imminent depletion for which cells must prepare in advance. Cells able to internalize such temporal correlations in their biochemical networks may benefit from higher fitness. We hypothesize that the Snf/Rgt/Mig network, responsible for glucose sensing and aerobic fermentation in yeast, has evolved such internalization within its complexity.In this project, we will address the dynamic signal-processing role of transporters Hxt1-7 and sensors (Snf3, Rgt2), each of which are expressed or activated at several glucose concentrations. If properly tuned, transporter expression could store information about past nutrient conditions. Moreover, sensors could exert synergistic responses when drops or rises in glucose concentration activate both. To explore these possibilities, we will simulate rising and decreasing glucose inputs with microfluidics, and will monitor the network components' response at a single-cell level with time-lapse


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Divergent roles of Smad1 and Smad2 in patterning the early mammalian embryo.
Funder: Wellcome Trust

Abstract: The TGF? secreted growth factors bone morphogenetic protein (BMP) and nodal play crucial roles in cell fate specification during vertebrate gastrulation. BMPs, acting via Smad1/5/8 induce 'posterior' or extra-embryonic mesoderm (including the germ cell lineage), whereas nodal signals through Smad2/3 specify the 'anterior' primitive streak and its derivatives. Genetic studies in mice suggest that dose-dependent signaling via Smad1/5/8 and Smad2/3 plays complementary roles in regulating cell fate allocation during gastrulation. Ablation of Smad1 primarily disrupts specification of extra-embryonic mesodermand formation of the germ cell lineage, whereas Smad2 functional loss results in defective gastrulation and enhanced formation of extra-embryonic mesoderm. The underlying causes of these complex tissue disturbances remain ill-defined.Information about Smad-regulated transcripts in the embryo is missing. To identify downstream Smad transcriptional targets, Smad1 and Smad2 mutant embryos will be characterized using a new panel of tissue-specific marker genes and profiled by microarrays and RNA-seq. These in vivo experiments will be complemented by investigation of the differentiation potential of mutant embryonic stem (ES) cells towards distinct cell fates in vitro. The transcriptional networks downstream of Smad1 and Smad2 in the early mammalian embryo also govern human development and disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Regulation of cell polarity by stress-response pathways
Funder: Wellcome Trust

Abstract: Regulation of cell polarity is implicated in various aspects of human health and disease, such as cell differentiation, immunity, and cancer progression. Cell polarity is also often lost as a result of response to a variety of cellular stresses. However, how reaction to stress mediates this phenomenon remains an unsolved biological problem. The proposed project aims at understanding the functional relationship between stress and maintenance of cell polarity in the model organism Schizosaccharomyces pombe. Our findings have set the basis for establishing a link between the activation of the S.pombe stress-activated protein kinase (SAPK) pathway and the activity of themaster regulator of cell polarity Cdc42. The first direction of the project focuses on identifying the proteins involved in the interaction and describingthe molecular processes by which they modulate Cdc42. Secondly, the project aims at characterizing the putative function of the actin cytoskeleton as a "sensor" for cellular stress. Preliminary research indicates that increase in monomeric actin concentration, as a result of disruption of the cytoskeleton,


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