NIHRDataInsights/HRCSData huggingface dataset:
Title: Patterning embryos with genetic oscillations.
Funder: Wellcome Trust

Abstract: The backbone's segmental anatomy forms in the vertebrate embryo by a remarkable process that defines the position of each vertebra with the tick of a genetic clock. When this clock fails, children are born with severe spinal malformation. Using zebrafish embryos to observe this clock ticking in real time, I will investigate the dynamics and the control of its molecular clockworks. I will investigate firstly how each of the cells ticks in isolation, secondly how these cells communicate with their neighbors so that they tick smoothly with a shared rhythm, and finally how the oscillations can be stopped and their time can be recorded to give a signal for the boundary of each newly forming vertebral body segment. These studies will give insight into the way our body axis segments. They will also suggest us how rapid changes in gene activity are controlled and coordinated in other important contexts such as inflammation and stem cell differentiation, where oscillations have just recently be en discovered.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Structural and enzymatic mechanism of how myosin-5 moves cargo in the cell
Funder: Wellcome Trust

Abstract: Molecular motors such as myosin operate under conditions where they are pulling against a load, yet they have only been imaged bound to actin under conditions where there is no load. We wish to visualize the effect of strain on the conformation of myosin-5 motor and lever arm domains and to understand how strain affects the myosin-5 kinetics at a single-molecule level. We also wish to study the elasticity and other structural properties of myosin-5 tail which presumably enables myosin to move cargo through meshworks of actin. We have devised a method for answering these questions using single-molecule biophysical techniques.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Chromosome segregation and cytokinesis in bacteria: mechanisms and regulation.
Funder: Wellcome Trust

Abstract: The cell cycle is one of the most fundamental and important processes in biology. I wish to elucidate how bacterial cells duplicate themselves using the exceptionally tractable model bacterium Bacillus subtilis. In bacteria the chromosome is replicated and daughter molecules are segregated in parallel with cell growth, requiring the huge DNA molecule to be highly organised and continuously remodelled. We wish to elucidate the mechanisms underlying chromosome compaction and folding. A major focus will be on the SMC complex, which is conserved from bacteria to man. We will also attempt to identify new chromosome organizing factors and elucidate their roles. How cells divide to generate identical daughters is also poorly understood. Division is governed by a filamentous protein FtsZ, which forms a ring structure at the future division site. There it recruits various other division factors that collectively drive constriction of the cell membrane and make the new cell poles. We wish to ide ntify the remaining factors required for division and its regulation, and then attempt to reconstruct functional elements of the machinery. The proposed research will have important implications for understanding many disease causing bacteria as well as providing critical information supporting the development of new classes of antibiotics.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Inferring human colonization history using genetic data.
Funder: Wellcome Trust

Abstract: DNA contains important clues about our ancestry, potentially allowing us to unearth detailed information on the movement of populations throughout human history. Technological advances have led to the cheap extraction of large amounts of DNA from individuals sampled from world-wide geographic regions. It still remains to develop efficient computational techniques to exploit the information contained in these vast new DNA resources. I will develop novel methods to infer details about human histor y using genetic data with greater precision and power than has yet been achieved. By carefully comparing unique DNA patterns among different world-wide groups, I will characterize how different populations relate ancestrally, infer details of human origins, and identify precisely when and where different geographic groups exchanged DNA (e.g. due to invasions or major migrations). Preliminary applications demonstrate the power of this approach, for example identifying DNA contributions from a gro up similar to modern-day Mongolians within individuals sampled in Central-South and East Asia and dating this contribution precisely to the era of the Mongol Empire of Genghis Khan and descendants. In addition to informing us about our unique ancestral history, my methodology will have important applications for DNA matching in forensics and genetics-based disease mapping studies among different populations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Development of statistical and experimental approaches to understand the roles of recombination and migration in human biology and disease risk.
Funder: Wellcome Trust

Abstract: 1. Recombination is a basic biological force which, with mutation, generates all our genetic variability. Our previous work focussed largely on gaining insights using genome-wide maps of recombination crossover rate. The proposed work focuses on different, unanswered questions: how, and why, does recombination vary across individuals? What is the effect of recombination, both crossover and more frequent non-crossover events, on the genome? How does recombination initiation (by PRDM9 binding) hap pen? We will use several powerful approaches: large variation datasets of Latinos and African-Americans, bioinformatic analyses, and experiments. To understand recombination's full effect, we will breed and sequence mice to build the first mammalian map of non-crossover (i.e. gene conversion alone) and crossover, in both sexes, to help: (i) understand broad-scale recombination location determinants. These are of interest for many reasons, and also affect human aneuploidy risk. (ii) quant ify non-allelic recombination events. Besides their inherent interest, they can produce disease-causing genomic rearrangements. (iii) better understand how recombination produces, and influences the fate of, mutations. To study recombination initiation, we will generate Chip-Seq data measuring PRDM9 binding, and combine with extensive information on chromatin structure and accessibility. 2. We will extend our existing approaches for inferring ancestry, to accurately infer ancestry at the Major Histocompatibility Complex (MHC) and identify whether ancestral patterns at this key disease susceptibility region are unusual. We will extend and apply new methods providing highly sensitive genetic ancestry information using haplotype sharing, to understand the structure of rare genetic variation and aid association tests using rare variants.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: UK human iPS cell consortium: genotype to phenotype.
Funder: Wellcome Trust

Abstract: As it becomes cheaper and faster to sequence the DNA of individuals in the population we are faced with two challenges. One is to discover which aspects of the genetic variation between individuals are compatible with good health and which are linked to increased risk of specific diseases. The other is that it is not always obvious why a particular genetic mutation causes a particular disease; if we knew the answer we would be better placed to devise new ways to treat that disease. A technique that can help us meet these challenges is to make stem cells, known as induced pluripotent stem (iPS) cells, from small samples of the skin or blood of healthy and diseased individuals. By comparing the DNA of iPS cells with the way the cells behave when grown in the laboratory we can understand how variation in our DNA results in variation in cell behaviour and use this information to identify new disease mechanisms The iPS cells and associated data that we generate will be freely available to researchers and doctors throughout the UK and will foster collaborations that will speed up the translation of research intoimproved diagnosis and treatment of disease.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Delineating the ageing proteome: Convergence of ageing pathways in Caenorhabditis elegans.
Funder: Wellcome Trust

Abstract: Recent observations have shown that animals with specific mutations that give them longer-than-usual life spans also appear to be resistant to age-associated illnesses like tumours and neurological disorders. However, the link between longevity and disease-resistance is not well-established as we still do not understand how ageing progresses at the molecular and cellular levels. Such an understanding will not only further our knowledge of this fundamental biological process, but will also allow us to develop strategies and drugs to promote healthy ageing by delaying the onset of age-related diseases. This will improve our quality of life and ease socio-economic costs associated with ageing by minimising the requirement for hospitalisation and care. In this study, I propose to use recent advances in protein quantification technologies to systematically study the ageing process by measuring changes occurring in cellular proteins as organisms age. In order to analyse this, I will calculat e fluctuations in the levels of proteins and the rates at which they are degraded within a cell, as well as their movements within cellular sub-compartments. Additionally, I will compare how long-lived, stress-resistant mutant animals differ from control animals as this is likely to lead to the identification of key proteins that regulate ageing.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The mechanism of membrane insertion of tail-anchored proteins.
Funder: Wellcome Trust

Abstract: All cells are surrounded by a membrane that separates the cells interior from the outside environment. Essentially all communication between cells relies on specialised proteins embedded within this membrane. These 'membrane proteins' comprise almost a third of all proteins in living organisms, and over five thousand are encoded within the human genome. Membrane proteins are responsible for everything from recognising hormones such as insulin, to detecting temperature changes, to regulating hea rtbeat. Defects in membrane protein function can lead to such disorders as cystic fibrosis, Alzheimer's disease, and muscular dystrophy. Despite their central importance in both health and disease, very little is known about how these proteins become embedded within the membrane. I propose to study this process for a class of membrane proteins called tail-anchored (TA) proteins. TA proteins are found in all organisms and are essential for controlling many cellular processes. Using several complementary techniques, I aim to determine the molecular details of how TA proteins are inserted into the membrane. Understanding this process will represent a critical scientific advance that will illuminate general principles of membrane protein insertion and may provide insight into a variety of diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Enhancing the cryo-electron microscopy capacity at Imperial College London for single particle and tomographic studies.
Funder: Wellcome Trust

Abstract: Electron microscopy (EM), especially cryo-EM single particle analysis technique, has become increasingly powerful in studying large macromolecular machines, due to the development in providing increasingly higher resolution structural information of large transient macromolecular complexes including the capability of capturing multiple functional states. The realization that many important macromolecular complexes are transient and intrinsically dynamic makes them not amenable to study by well-e stablished structural biology techniques such as X-ray crystallography. Cryo-EM, on the other hand, requires relatively small amount of samples and can capture transient and distinct functional and conformational states. With the development of algorithms that deal with heterogeneous populations within samples, cryo-EM single particle analysis becomes the ideal method for studying the complex dynamics of many key macromolecular machines. Furthermore, the ability to image organelles and sections of a cell at high resolution will enable the investigations of individual macromolecular complexes to be placed in a cellular environment, thus bridging structural molecular biology with cell biology and physiology. To achieve this, we need a modern high resolution and high sensitivity electron microscope that is capable of obtaining high quality data in an automated fashion.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The DGVa a database for genomic structural variation.
Funder: Wellcome Trust

Abstract: The Database of Genomic Variants archive (DGVa) is a repository that provides archiving, accessioning and distribution of publicly available genomic copy number and structural variants (CNV/SV) in all species. DGVa is a centralised and integrated resource that distributes data in a consistent format using applicable data standards and a data model specifically designed to capture the intricacies and richness of current CNV/SV discovery and genotyping experiments. DGVa works closely with the Uni versity of Toronto's Database of Genomic Variants (DGV), who themselves provide a curated set of high-quality CNV/SV data to be used as a reference normal set in the context of human disease studies and screening for diseases associated with large-scale chromosomal lesions. DGVa provides data directly to Ensembl, BioMart and other EBI resources. Datasets accessioned at the EBI (including those from the 1000 Genomes Project and WTSI's Mouse Genomes Project) are used by researchers around the wor ld. DGVa is the European peer database with the dbVar resource at the NCBI. In addition to sharing data between the two archives, DGVa works closely with dbVar on all aspects of the CNV/SV data model, submission format, data descriptions using ontologies and data presentation. DGVa is available from the EBI at http://www.ebi.ac.uk/dgva


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE
Title: Chemistry in Cells.
Funder: Wellcome Trust

Abstract: We request funding for an automated Bruker 600 MHz NMR spectrometer with a multinuclear cryogenic probe and a Thermo LTQ XL hybrid Fourier Transform Mass Spectrometer with UHPLC system. The instruments are essential elements of our Chemistry in Cells initiative, of which a major objective is to address the urgent need for quantitative analyses of small molecules in cells and to define ligands for small-molecules in cells. Chemistry in Cells brings together new combinations of investigators to ad dress critical problems in biomedical science. Specifically, the requested state-of-the-art instrumentation will enable us to broaden the links between Wellcome investigators and synthetic chemists. Critical in this regard is Oxford Synthesis Connections, which is directed by two co-PIs, and connects Wellcome researchers in biomedicine with 15 Oxford chemists who can prepare reagents and analyse metabolites by methodologies beyond most biological and medical laboratories. Key scientific objectiv es of Chemistry in Cells include relating perturbations in metabolite levels with disease, developing and applying new methods for identifying small-molecule ligands, and developing innovative molecular probes. In addition to the specific projects outlined in the proposal, Chemistry in Cells is designed to generate a melting pot of scientific cultures that will produce new discoveries.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: A centralized platform for validation of genomic and epigenomic targets from clinical and non-clinical studies.
Funder: Wellcome Trust

Abstract: Over 1000 associations have recently been identified in over 100 traits and common human diseases using GWAS/EWAS. To further advance this research towards identification of the underlying causal variations for therapeutic targeting, requires follow-up on several levels. In the first instance, the identified associations need to be validated, ideally by an independent method and in additional samples. Secondly, the haplotypes, hepitypes and other genomic intervals in which the associations were found need to be further analysed for functional variations in as many samples as possible. The main objective, therefore, is to establish a centralized high-throughput facility for validation and targeted functional analysis that is directly compatible with next-generation sequencing, the method of choice for downstream processes. We believe that the requested equipment from RainDance Technologies satisfies all the technical requirements for accuracy, sensitivity and specificity. It also curre ntly offers best value with respect to throughput, flexibility and future integration with GCLP settings which is a requirement for clinical and future personalized medicine programmes. Under the guidance of the lead applicant, the experienced UCL Core Facility (UCL Genomics) will operate and maintain the equipment ensuring fair access to the 20 named co-applicants and collaborators and beyond if capacity allows.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: Cell Sorting Flow Cytometry for the Study of Live Cell, Cell Surface and Intracellular Processes.
Funder: Wellcome Trust

Abstract: This research proposal brings together six groups from two Life Science Departments at the University of Bath, spanning the regulation of the immune system, tissue development and regeneration. This proposal is centred on the common technical requirements of investigators working towards specific objectives: - Genetic Analysis of Inflammation in the Drosophila embryo - Endothelial Colony-Forming Cell culture for tissue engineering - Signaling pathways that determine differentiation of CD4 + T helper lymphocytes - Molecular control of embryonic stem cell fate - Differentiation of hepatic endoderm to biliary epithelial cells - Towards a complete description of the melanocyte gene regulatory network There are shared interests in each of these research themes including phosphoinositide signalling, transcriptional regulation, cell fate choice, immune cell motility and inflammatory disorder. The applicants research needs are extending into areas that require reliable separation and analysis of mixed cell populations using advanced cell sorting flow cytometry. No other technology is able to purify heterogeneous cell populations with an equivalent speed and accuracy. The presence of a state-of-the-art FACS sorter (BD FACS ARIA III) on-site will greatly enhance the experimental potential and productivity of the applicants. Cell sorting capability, along with exchange of expertise and novel approaches, will also enable us to extend collaborations.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: guidetopharmacology.org- a peer-reviewed online resource giving information ondrugs and their targets
Funder: Wellcome Trust

Abstract: The revolution in genomics and molecular genetics has led to the identification of many novel approaches to the development of new medicines. However, there is an urgent need for an accessible and authoritative online synopsis of the complete landscape of existing and future drug targets, to foster innovative drug discovery and provide an integrated educational tool for academia, industry and the interested public. We developed two complementary resources providing key information on drugs and t heir targets: the IUPHAR database (IUPHAR-DB) and the BPS Guide to Receptors and Channels (GRAC) and integrated them into a new open access portal, guidetopharmacology.org, which documents the pharmacology and functions of the targets of about half of all current licensed drugs. We request support from the Wellcome Trust, with shared funding from IUPHAR and BPS, to develop guidetopharmacology.org to encompass all the human targets of current prescription medicines and the likely targets of futur e medicines. Developed by experienced curators, supported by a large international network of expert volunteers and peer-reviewed by NC-IUPHAR, the resource would identify the key pharmacological properties of each drug target, with accurate quantitative and chemical information from the primary research literature and extensive links to other online resources.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE
Title: HWB NMR: a national resource for biomolecular research.
Funder: Wellcome Trust

Abstract: We aim to ensure that the UK remains a world leader in biomolecular NMR spectroscopy by providing external academic users with open access to a state of the art 900 MHz NMR system for their research. We request funding to upgrade our Varian INOVA 900 MHz spectrometer to the latest standard including a new console and latest generation cryogenic probe set for highest sensitivity detection of 1H/13C/15N resonances. We will dedicate at least 70% of the available time to an established community of academic users based in the UK and beyond. The support would enable the staff at the Henry Wellcome Building for Biomolecular NMR Spectroscopy (HWB-NMR) to offer fast methods for assignment and analysis of structures, interactions and dynamics . We will also advance the standards, throughput and cost effectiveness of NMR spectroscopy, disseminating recent developments across the NMR community. The next generation of researchers interested in structural biology and drug discovery will be trai ned using these NMR systems and methods within a centrally located national facility that offers courses, workshops and collaborative support to its users, thus fostering continued scientific excellence and impact in biomedical research.


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