NIHRDataInsights/HRCSData huggingface dataset:
Title: An integrative, multiscale approach to understanding the molecular basis for receptor mediated trafficking within the early secretory pathway.
Funder: Wellcome Trust

Abstract: The movement of proteins within eukaryotic cells is an essential process that maintains internal organelle integrity and underpins normal cell function. Despite the identification, several decades ago, of the receptors controlling protein trafficking, the molecular mechanisms of selective retention and export of ER and Golgi resident proteins still remain poorly understood. However, this recently changed when our study on the KDEL receptor revealed the structural basis by which a trafficking receptor can signal across a membrane to cytoplasmic coat protein complexes to initiate retrograde trafficking. We now aim to determine the mechanisms that underpin protein trafficking by other receptors within the early secretory pathway. We have developed an integrated approach involving cell biology and structure-based methods, including lipid-based crystallisation and single particle cryo-electron microscopy coupled with advanced protein engineering, super resolution light microscopy, and multiscale molecular dynamics analysis of trafficking complexes. Specifically, we will determine the mechanism for several cargo-receptor systems that control anterograde and retrograde protein sorting and address how sorting receptors recognise cargo proteins, and the mechanism(s) by which these receptors signal across membranes. Ultimately, we expect to understand the molecular basis for cellular trafficking, providing fundamental insights into crucial pathways involved in human protein folding diseases.

Lay abstract: Eukaryotic cells concentrate certain proteins in the lumen of the endoplasmic reticulum (ER), whereas others are actively exported for secretion. For 20 years, cell biologists have known the identity of the receptors responsible for this process, but the molecular basis for their function has remained elusive, hampering efforts to understand this fundamental feature of cell biology. Using a combination of atomic structural models, cell and biochemical assays, computational molecular dynamics and synthetic antibody technology we are now able to address many of the outstanding questions relating to receptor mediated trafficking. Answers to these questions will provide a comprehensive molecular basis for how proteins are trafficked within the cell and understand the neurological and ageing related diseases that result in malfunction of these processes.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Whole genome sequence based analysis of genetic variation and genome evolution
Funder: Wellcome Trust

Abstract: DNA sequencing is a core technology for modern biomedical science, and our ability to sequence genomes with ease and use that information efficiently is still unfolding. I propose first to build new bioinformatics data structures and software to map sequence data, call genetic variants, and integrate phasing and imputation, scaling to millions of samples with high accuracy and making best use of new long read sequencing technologies. These will be based on sequence variation graphs and haplotype panels over them, effectively exploiting already-discovered genetic variation in the population. Second I will develop new statistical methods to infer the evolutionary history of genome sequences to identify ancestral populations, model gene flow between them, and date and place mutations into them. I will apply these methods to modern and ancient samples to elucidate Eurasian and African human population history. Finally, I will apply these methods to new data I collect from the Lake Malawi adaptive radiation of over 500 species of cichlid fish, to infer the evolutionary relationships in the radiation, test models of speciation, and identify genes involved in cranio-facial adaptation. These studies will empower future use of sequencing data in biomedicine, and advance our understanding of genome structure and evolution.

Lay abstract: Our ability to sequence genomes, exemplified by the human genome project, has enabled us to read directly the information in our DNA that underlies life, and has led to major medical advances and direct clinical applications in genetic disease and cancer. Continuing advances in technology create many opportunities in biomedical and evolutionary science, but require new computational methods to effectively use the data. In this proposal I will develop those methods, which will exploit our accumulated knowledge of genetic variation in the population, using advanced computing technology to allow them to scale to millions of genome sequences. As well as methods to efficiently measure genetic variation I will develop new statistical approaches to understanding the evolutionary relationship between genome sequences, and with them illuminate the genetic history of humans in Europe and Africa, addressing key questions about how modern humans are related to each other and to our ancestors. Finally, I will use these new technical opportunities and methods to study speciation, natural selection and genetic adaptation, by studying the most dramatic evolutionary radiation of vertebrates, of many hundreds of cichlid fish species in the East African great lakes.

Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: How are chromosomes held together by cohesin?.
Funder: Wellcome Trust

Abstract: 1. How are chromosomes held together? 2. How does cohesin associate with chromatin and hold sisters together? 3. Mechanism of loading? 4. How is cohesion established? 5. How is dissociation regulated by acetylation? 6. Whatis the role of kinetochore cohesin during meiosis? 7. What is the structure ofcohesin and partners? 8. How does condensin hold together the DNAs of individual chromatids?


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The role of non-histone proteins in chromosome structure and function during mitosis
Funder: Wellcome Trust

Abstract: I propose to study how a set of key proteins (condensins I/II, cohesin, Kif4A, topo II&alpha;) mold the chromatin fibre into its characteristic rod-shaped helix of loops in mitosis. Using a transformative system allowing us to obtain cultures entering mitosis with near-perfect synchrony we will adopt an interdisciplinary approach involving genomics (Hi-C, Capture-C, cut&run), proteomics, crosslinking, microscopy and molecular modelling to resolve changes in chromatin fibre and chromosomal protein organisation on a minute-by-minute basis during mitotic entry. Using non-toxic synchrony methods plus acute (and reversible) protein depletion with auxin degrons, we will determine when, where, how and with whom these proteins act to shape mitotic chromosomes. Access to the single copy chicken Z chromosome with its unique-sequence centromere allows us unprecedented mapping of the chromatin folding and protein distribution at a vertebrate centromere during this process. Following our discovery that RNAs mediate assembly of the mitotic chromosome periphery compartment (MCPC) downstream of Ki-67, we will initiate a new research direction identifying the proteins and RNAs involved, and determining their functional significance for chromosome segregation. Lastly, we will optimise methods for isolating human artificial chromosomes (HACs), avoiding unwanted DNA rearrangements that endanger future synthetic genome efforts.

Lay abstract: A chromosomal DNA molecule can be imagined as a wardrobe packed with clothing. When we want to move that clothing (i.e. to split/segregate the chromosomes between two daughter cells during cell division) we put it in a suitcase, in our analogy a mitotic chromosome. Exactly how the genome is compacted to form mitotic chromosomes is not fully understood. My team will use a range of experimental approaches to understand how chromosomal DNA is compacted 10,000-fold and organised by scaffold proteins into rod-shaped mitotic chromosomes. We will also study the structure and function of the suitcase itself, a layer of proteins and RNA called the chromosome periphery, and the assembly and disassembly of its handle - the kinetochore. Knowledge obtained in these studies will help us better understand the process of chromosome segregation, defects of which cause a range of important human health problems ranging from birth defects to cancer.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: X chromosome inactivation; linking mechanisms for in cis accumulation of Xist RNA and chromosome silencing.
Funder: Wellcome Trust

Abstract: This proposal aims to understand the fundamental molecular mechanisms that underpin X-inactivation, the process that evolved in mammals to equalise gene dosage in XX females relative to XY males. X-inactivation is orchestrated by a functional non-coding RNA, Xist, which accumulates locally over the chromosome from which it is transcribed and silences underlying genes. We have made significant progress towards understanding Xist-mediated chromosome silencing pathways, but key gaps remain, notably in defining a principal late-acting pathway required to complete silencing of a significant subset of X-linked genes. Additionally, we currently have only a very limited understanding of how Xist RNA accumulates in cis over a single chromosome territory. Thus, we set out a series of experiments to resolve these questions, making use of state of the art methodologies in genomics and proteomics to define the late-acting silencing pathway, and advanced cellular imaging coupled to genetic perturbation to define mechanisms for local accumulation of Xist RNA. Bringing these two goals together, we will determine sufficiency of the known factors and test our models for their mode of action by in vivo expression of synthetic transcripts to which we will tether key factors for silencing and RNA accumulation.

Lay abstract: Mammals have evolved a process termed X-inactivation to equalise levels of X chromosome genes in XX females compared to XY males. Thus, a single X chromosome is switched off during early female embryogenesis. Our goal is to understand the molecular mechanism of X-inactivation. Our previous studies have shown that X-inactivation is orchestrated by an unusual and remarkable non-coding RNA molecule, termed Xist. Xist RNA is expressed from a single X chromosome in female cells and then accumulates locally over the entire chromosome territory. Localised Xist RNA recruits factors that silence underlying genes by modifying chromatin structure. This proposal is aimed at discovering key factors required for local accumulation of Xist RNA and for Xist-mediated silencing, and determining their mode of action. Ultimately we will apply synthetic biology approaches to demonstrate that the pathways we have identified are sufficient to recapitulate Xist function in cells.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Exploring accessible nodes in the Unfolded Protein Response
Funder: Wellcome Trust

Abstract: Proteins are comprised of linear chains of different amino acids, the order of which is specified by the genome. Functionality of these key building blocks of life requires that the protein chain fold onto itself to create a three-dimensional object, whereas incorrect (mis)folded proteins may be toxic to cells. The accumulative burden of generating properly folded proteins from newly-synthesized unfolded ones is believed to contribute to aging and its attendant diseases. This is especially conspicuous in the endoplasmic reticulum (ER), a small compartment in which proteins that are destined to function outside cells are folded and processed. Cells are endowed with an apparatus for coping with the burden of unfolded proteins in their ER, but the implementation of this unfolded protein response (UPR) entails important tradeoffs: This system, which developed over a billion years, is apparently not optimized for longevity (its edges expose failures of homeostasis). We aim to uncover nodes in this regulatory network that can be enfeebled or augmented to therapeutic ends. In practice this entails discovering specific components of the UPR that can be tweaked with chemicals in the hope that these will optimize the system to the needs of long-lived humans and their companion animals.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE
Title: BSA - public engagement with health research
Funder: Wellcome Trust

Abstract: The British Science Association is proposing a new funding scheme to support public engagement with health in the UK. This new fund will: take a more outcomes-focussed and targeted approach to working with applicants; support and foster innovation; and encourage the sector to diversify its approaches and audiences. We are proposing a three in one scheme: an ‘Incubator Fund’ will provide smaller grants to support innovation and diversity, the ‘Main Fund’ will establish and expand proven links and approaches, while a ‘Discretionary Fund’ will allow us to invest in organisations or approaches that show particular promise. As a result, the public engagement with health sector will benefit from a grants scheme that’s more flexible and easier to navigate. This will help support and diversify the applicant pool, and hence benefit the public who will be more empowered to engage in research and better equipped to interact with health researchers, or people in allied careers, on topics they’re interested in. Ultimately more people in the UK will be engaged with - and trusting of - health research, and be able to access its benefits.


Research activity codes: 1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: GENERIC HEALTH RELEVANCE
Title: How centromeres are specified: the interplay between heterochromatin, CENP-A chromatin, and kinetochore assembly.
Funder: Wellcome Trust

Abstract: Rather than being hard-wired , the sites chosen for centromere formation are surprisingly plastic and epigenetically regulated. Key to this regulation is the replacement of histone H3 with CENP-A to form unusual nucleosomes that mark centromeres as sites for kinetochore assembly. But what distinguishes na ve centromere DNA to trigger CENP-A incorporation? We discovered that heterochromatin is required to direct CENP-A establishment on adjacent centromeric DNA in fission yeast. We will dissect the contribution of key histone modifying activities in forming heterochromatin and CENP-A chromatin. We will test if CENP-A nucleosomes favour centromeric DNA over other sequences, and if these properties are conserved in related, non-homologous, centromeric DNA. We will investigate how intrinsic features, such as transcription, provoke H3 eviction in favour of CENP-A incorporation. We will couple the induction of heterochromatin, and CENP-A chromatin, on plasmid-borne centromeric DN A with plasmid affinity selection, ChIP-seq and quantitative proteomics. These unique tools will allow us to determine the temporal dynamics and the full repertoire of events that accompany and result in heterochromatin formation, CENP-A deposition and kinetochore assembly. By manipulating cells we will uncover the molecular mechanisms by which heterochromatin, primary DNA sequence and transcription contribute to the establishment and propagation of functional centromeres.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Standards for official statistics on climate-health interactions
Funder: Wellcome Trust

Abstract: This proposal is for a collaboration between the Office for National Statistics (with the UK Health Security Agency and the Cochrane Climate-Health Working Group) and two national statistical institutes in the African region, to develop a transparent and globally generalisable framework and technical platform for official statistics on climate change, environment and health, and a set of statistical methods to better estimate climate-related health risk using real world data sources, including modelling local-level impacts. By addressing the current lack of harmonised approaches, developing new methods in close partnership with LMICs and building capability, the project will advance global research on climate and health, help to address gaps in the knowledge base and support national monitoring and evidence-based policy. Users of the outputs will include government and NGO decision-makers who will be able to access information to guide interventions in clearer, more comprehensive and more actionable forms; producers of official statistics, especially in LMICs, whose ability to monitor effects of climate change will be increased by provision of practical, coherent standards and open source tools; and producers and consumers of climate change research who will benefit from faster study development based on shared approaches and more consistent ‘language’ for systematic communication.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Wellcome Trust PhD Programme for Primary Care Clinicians
Funder: Wellcome Trust

Abstract: Primary care is central to the provision of health care in the NHS, accounting for more than 90% of patient contacts every year. Recent changes to the organisation of the NHS has placed general practice at the centre of reform. It is imperative to develop a strong clinical academic workforce to generate research evidence to underpin high-quality extramural care, and provide multidisciplinary academic leadership to clinical colleagues. The Wellcome PhD Programme for Primary Care will provide strategic investment to support the development of a strong cohort of clinical academics, providing high quality training in internationally renowned applied research units and supporting capacity development in a critically important but still under-resourced field. Our expertise in a broad range of clinical and methodological areas maps to national research priorities and provides a platform for innovative translational research that will span and break down traditional barriers between professions and health care settings whilst developing the next generation of primary care scientists. Our proven track record in supporting academic careers demonstrates our commitment to ensuring that Fellows will receive the highest quality research training together with extensive mentoring and networking opportunities enabling them to become our future research leaders.

Lay abstract: No Data Entered

Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: 4ward North Clinical PhD Academy
Funder: Wellcome Trust

Abstract: We request a Wellcome Trust (WT) Clinical PhD programme between the Universities of Leeds, Manchester, Newcastle and Sheffield (N4) with a feeder year for selection followed by a three-year WT-funded PhD period. Our key goals are to: 1. Attract a national cohort of the best clinical trainees across all specialties. 2. Deliver excellence in research training as if one institution with coherent access to the best N4 supervision, technologies and facilities across disciplines and reaching industry. 3. Equip the next generation of clinical academics with the contemporary strategic skills available across N4 to address the major healthcare challenges of the future with innovative answers. 4. Improve N4 acquisition of other clinical PhD awards (e.g. from MRC) because of standards raised by this WT programme. 5. Establish impactful publication records for each trainee that sustain high-level career development. 6. Create high quality bespoke pathways for seamless individual transition into postdoctoral clinical academic training with innovative pull-through to intermediate fellowship (e.g. our programme with the Francis Crick Institute). 7. Establish a culture, mentorship, and clear routes and processes built on best practice to ensure a sustainable pipeline of internationally-leading clinical academic trainees across northern England.

Lay abstract: No Data Entered

Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: GENERIC HEALTH RELEVANCE
Title: Pathways to Equitable Healthy Cities (London Hub for Urban Health)
Funder: Wellcome Trust

Abstract: The London Hub for Urban Health, Sustainability and Equity aims to be the world’s foremost transdisciplinary hub for research, training and pubic engagement on urban health. It is founded on two constituent projects – Complex Urban Systems for Sustainability and Health (CUSSH) and Pathways to Equitable Healthy Cities (PEHC) – and involves leading London-based institutions and their global network of collaborating institutions. The Hub’s principal objective is to integrate and coordinate research and stakeholder engagement that support evidence-based policies aimed at improving population health, health equity and environmental sustainability in cities around the world. The Hub, and its projects, will achieve this objective through comparative studies that involve participatory research and coproduction of knowledge among academic researchers, policy makers and practitioners, and civil society; developing models for prospective policy evaluation and applying these models to data from our partner cities; and training the next generation of research and policy leaders in urban health, while establishing the foundations for sustaining and expanding the Hub beyond the Wellcome funding period. The PEHC project focuses on how policy scenarios that involve changes to key urban sectors and services impact population health and health inequality in Accra, Beijing, Dhaka, London, Tehran and Vancouver.


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