NIHRDataInsights/HRCSData huggingface dataset:
Title: Nuclear genomic control of mitochondrial DNA heteroplasmy in humans: population genetics & disease
Funder: Wellcome Trust

Abstract: Human mitochondrial DNA (mtDNA) mutates ~15-fold faster than nuclear genome, but only ~5% of the 16.5Kb mtDNA shows genetic variation in the population. Severe mtDNA mutations cause diseases affecting ~1 in 5000, but it is not known how new genetic variants arise, and why some are more common than others. We aim to address these two questions, building on pilot data implicating a mechanism acting on mtDNA during female germ cell development. Most humans inherit a mixed population of mtDNA (heteroplasmy) from their mother, and the proportion of mutated molecules can either increase or decrease within one generation due to a ‘genetic bottleneck’. This accelerates the segregation of alleles during early germ-cell development. We aim to: (a) define the mechanism of the bottleneck in germ cells; (b) identify the nuclear transcriptional signal controlling the bottleneck; (c) determine whether selection for/against particular mtDNA mutations occurs at the level of the cell, mitochondrion, or mtDNA molecule; and, (d) identify nuclear genes modulating the rate of segregation and selection. Together this work will define the fundamental biology driving mtDNA genetic variation in the human population, explain how this leads to mitochondrial diseases, and identity new approaches to prevent and treat these disorders.

Lay abstract: Mitochondrial DNA (mtDNA) mutations are an important cause of inherited disease, but it is not known how they arise, nor why some mutations are more common than others. Our pilot work implicates a mechanism controlled by the nuclear genome, which acts on the female germ line (egg cells) during embryo development. We aim to define the mechanism of inheritance of mtDNA, and understand how the cell nucleus controls this. We will discover why some mtDNA mutations are suppressed, and how other mtDNA mutations are preferentially inherited. This will cast light on the fundamental biology driving mtDNA genetic variation in the human population, and why this sometimes causes mitochondrial diseases. In the process, we will identify new targets to treat or prevent mtDNA disorders. Given emerging evidence linking mtDNA mutations to age-related neurodegenerative diseases, these findings will also have important implications for human health in an ageing population.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Centriole and centrosome assembly
Funder: Wellcome Trust

Abstract: Centrioles and centrosomes have many important roles in eukaryotic cells, and their dysfunction has been linked to various human diseases, ranging from cancer to dwarfism. Our overarching goal is to understand how these organelles assemble and function at the molecular level. We have developed sophisticated imaging and computational methods to quantify the dynamic behaviour of fluorescently-tagged proteins in the early, syncytial Drosophila embryo, where hundreds of centrioles and centrosomes synchronously assemble every few minutes. This has allowed us to quantify the behaviour of individual proteins during the assembly process with a precision that is currently not possible in any other system. We are deriving mathematical models of the assembly processes and testing them by combining the powerful genetics available in flies with our precise measurements that allow us to detect even subtle changes in assembly kinetics. Our recent studies have led to several surprising and important discoveries—most notably that centriole assembly is timed and executed by a centriole-associated oscillator. Our work will ultimately generate a complete molecular and mathematical description of centriole and centrosome assembly in flies. We expect that the principles we discover will apply to centriole, centrosome and organelle assembly in other systems.

Lay abstract: Centrosomes are tiny intracellular structures that help organise the cell's "skeleton" . Centrosome dysfunction has been linked to several human diseases, including cancer. We study how centrosomes assemble in flies, where we have developed sophisticated methods that allow us to visualise and measure how proteins incorporate into assembling centrosomes. We are deriving mathematical models of the assembly process and are testing them in mutant flies in which specific centrosome proteins have been altered to see how the alteration affects centrosome assembly. Our studies have led to several important discoveries—most notably, that centrosome assembly is regulated by a molecular "clock". This is the first demonstration that a clock can regulate the assembly of a cell structure. We aim to understand how this clock regulates centrosome assembly, and test whether clocks might regulate and coordinate the assembly of other cell structures.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Targeting membrane proteins in their native environments - Mass spectrometry meets cell biology
Funder: Wellcome Trust

Abstract: The overarching goal of my research is to understand the relationship between membrane proteins and their lipid surroundings. This is important since many membrane proteins are unable to retain their structure and function when extracted from their native environment and reconstituted into a membrane mimetic. Dynamic proteins, for example G-protein coupled receptors, solute carriers and sigma receptors, are intimately connected to their membrane environments and prone to loss of function and activity in detergent micelles. To overcome this disconnect we will develop and apply our mass spectrometry approaches to examine dynamic drug targets within their membrane context. Our key goals will be to challenge these receptors and transporters with agonists, antagonists, inhibitors and lipids effectively in situ. Examples include solute carriers which during tumour progression respond to the need for an altered metabolism by increasing expression. Analogous methods will be used to uncover the targets of mitochondrial and lysosomal therapies. Many of our research themes converge on consequences of the COVID-19 pandemic. While this remains an area of intense scientific scrutiny we will focus on the less-studied receptors and ‘infection enhancers’, and contribute to understanding the roles of lipids in the endocytosis and viral recognition pathways.

Lay abstract: Embedded in the membrane of a cell, or circulating in the blood stream, are thousands of different lipids involved in a wide range of biological processes. These lipids interact with proteins to both regulate and control their structure, function and location. How these control mechanisms change during health and disease progression is difficult to ascertain. We will develop mass spectrometry methods to study critical drug targets that are influenced by their membrane environments. These targets include receptors involved in vision, transporters implicated in cancer and mitochondrial diseases as well as those involved in cellular entry and destruction of viral particles. The expected outcomes will include a new way to study the impact of drugs in vision, a greater understanding of transporters involved in cancer, new knowledge of lysosomal and mitochondrial disorders as well as a deeper understanding of additional factors involved in COVID-19 coronavirus propagation and entry.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular basis of lipid traffic at interorganelle contact sites
Funder: Wellcome Trust

Abstract: One unsolved mystery of cell biology is how lipids, made in the endoplasmic reticulum, travel to other cellular membranes. This question, originally deemed solved by the discovery of vesicular traffic, was recently spotlighted by the discovery of membrane contact sites (MCS), at which lipid transport proteins (LTP) accumulate. LTPs solubilize and transport lipids between two membranes in vitro. The role of LTPs in vivo is, however, more mysterious, because lipid exchange appears to be a highly redundant process, challenging standard genetic screens. I hypothesize that redundancy allows lipid rerouting to allow proper lipid fluxes in different conditions. But this hypothesis is challenged by another limitation: no method allows to measure lipid fluxes inside the cell. I propose to develop two methods to circumvent these problems. First is a synthetic-biology approach: bacterial proteins are targeted to different organelles in a eukaryotic cell to modify lipids within these organelles and assess lipid fluxes between compartments. Second is a transposon approach that allows identifying genes that become essential when other genes are missing. Combining these approach will yield unprecedented insight into this unsolved issue. Because lipids are often dysregulated, our research will shed light on the biology of many diseases.

Lay abstract: Biological membranes are crucial to the function of a cell. Not only do they tightly separate the interior of the cell from the external world, they also compartmentalize the cell by bounding several substructures within the cell, called organelles. Membranes are mostly constituted of stacked lipid molecules. Although as crucial for life as DNA or proteins, lipids are much less studied and understood. While we know where lipids are made, we do not, for instance, understand how they reach the cell membrane and that of many organelles. I will develop innovative tools to address lipid transport at the genetic and biochemical level. These studies will uncover the mechanisms for the distribution of lipid molecules necessary for the healthy function of the cell.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: The OpenSafely Research Platform
Funder: Wellcome Trust

Abstract: OpenSAFELY is a new secure analytics platform for electronic health records in the NHS, created to deliver urgent results during the global COVID-19 emergency. It is now successfully delivering analyses across more than 24 million patients’ full pseudonymised primary care NHS records, with more to follow shortly. All our analytic software is open for security review, scientific review, and re-use. OpenSAFELY uses a new model for enhanced security and timely access to data: we don’t transport large volumes of potentially disclosive pseudonymised patient data outside of the secure environments managed by the electronic health record software company; instead, trusted analysts can run large scale computation across live pseudonymised patient records inside the data centre of the electronic health records software company. This pragmatic and secure approach has allowed us to deliver our first analyses in just five weeks from project start.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE
Title: Factors Determining Clonal Selection in Germinal Centres
Funder: Wellcome Trust

Abstract: Antibody affinity maturation occurs in germinal centers (GCs) through iterative rounds of somatic hypermutation (SHM) in dark zones (DZs) and selection in light zones (LZs). Current models state that, following SHM, DZ cells exit cell cycle and move to LZs to test their newly mutated B cell receptors by competing T cell help. High affinity B cells preferentially “win” in receiving help, and this causes them to undergo cyclic reentry (defined by S phase initiation and DZ re-entry). We recently demonstrated the possible existence of a second checkpoint, because BCR expression is required for LZ entry. We propose testing the nature of BCR-dependent signals required for this (e.g. cognate vs tonic signaling). Next, we will re-examine the fundamental principle that affinity enhancements are favored by LZ cells competing for cyclic re-entry promoting cues. In unpublished studies, we unexpectedly find that T cell help in not required for initiating cyclic re-entry. We will therefore test whether LZ cells compete for other non-T cell-derived cues, or whether instead cyclic re-entry is controlled independently of selection events. Finally, we will investigate whether GCs utilize innate cell types and signaling pathways for sensing the continued presence of foreign material and for determining GC longevity.

Lay abstract: Most vaccines work by eliciting antibody-mediated immunity. Antibodies bind and “neutralize” important sites on pathogens, however achieving this represents an enormous challenge for B cells; it requires recognizing an almost infinite number of antigens, including many that are purposely difficult to reach. B cells overcome these hurdles by generating bespoke antibodies for each new infection they encounter through a remarkable process known as antibody affinity maturation that occurs within germinal centres (GCs). Here, GC B cells mutate their antibody-encoding genes and select those antibodies that bind best. However, the details of how selection occurs in GCs remains poorly understood. Using novel genetic tools that allow us to track the movement of cells between stages and events, we will investigate the fundamental principles underpinning this process. Antibody affinity maturation is often described as being a form of rapid Darwinian evolution; we hope to understand the selective pressures that drive this.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Planar polarity as a model for understanding self-organisation from molecular to tissue scales
Funder: Wellcome Trust

Abstract: A fundamental objective of developmental biology is to understand self-organised patterning, whereby individual molecular interactions at the nanometre scale contribute to tissue patterning beyond the millimetre scale. Significant challenges in achieving this are following the localisation and interactions of individual molecules in living tissues, and showing the sufficiency of particular interactions to drive tissue patterning. We study a simple in vivo model: the ability of cells in the Drosophila wing epithelium to self-organise to coordinate their polarity with their neighbours (‘planar polarity’). Decades of research have identified key proteins, but how their molecular interactions lead to planar polarity remains unresolved. To move forward, we will exploit multicolour single molecule microscopy and precise spatiotemporal manipulation of gene function in the developing wing. In parallel, we will reconstruct molecular behaviours in heterologous cell culture. We will investigate processes occurring at different size scales, that when integrated lead to tissue planar polarisation. Specifically, how: (1) planar polarity proteins mediate molecular symmetry breaking at the nanometre scale by assembling into asymmetric intercellular complexes (2) local protein sorting mechanisms organise protein complexes into polarised domains tens of nanometres in size (3) cellular self-organisation mechanisms segregate protein complexes to opposite cell edges at the micrometre scale

Lay abstract: The development of the organs of our bodies requires many different types of cells to be organised into complex structures. Remarkably, rather than being directed by an external blueprint or map that tells each cell where to go, much of the arrangement of cells in our bodies arises via a process known as ‘self-organisation’, whereby cells communicate with their neighbours to arrange themselves into simple patterns. We study one of the simplest forms of self-organisation of cells: a process called ‘planar polarity’, in which cells in a flat sheet all align themselves to point in the same direction. Pioneering genetic studies in the fruitfly have identified many of the genes involved, which produce proteins that mediate the coordinated alignment of cells. In this project we will seek to understand how the action of individual proteins within cells can lead to them aligning themselves with their neighbours, in a self-organising manner.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Understanding the diverse molecular mechanisms of chromatin-targeted histone deacetylase complexes
Funder: Wellcome Trust

Abstract: Eukaryotic gene regulation depends upon a plethora of multi-protein complexes that both control the organisation of chromatin and establish specific patterns of post-translational modifications of histone tails. These histone marks are key to the processes of gene regulation. Deciphering the roles and mechanisms of the complexes that regulate chromatin is one of greatest challenges in understanding how genome activity is controlled. We aim to understand the roles and mechanism of action of a family of essential, non-redundant histone deacetylase complexes that control chromatin accessibility across the genome. These HDAC complexes share a common catalytic engine, but contain very different accessory proteins and have diverse oligomeric states. Although these are essential complexes, conserved from nematodes to man, we have only a very limited understanding of their mechanism of action. We will take two approaches to determine the mechanisms through which these complexes engage with their chromatin substrates and to understand how this determines their biological function. We will use structural techniques to determine the architectures of three exemplar complexes in complex with chromatin. We will use genomic and proteomic techniques to explore how these structures mediate their distinct biological activities.

Lay abstract: Our genetic material, DNA, is wrapped around histone proteins to form nucleosomes which are packaged together to form chromatin. Chromatin can exist in an open state in which genes are active or a closed state in which genes are repressed. We are studying a family of enzyme complexes (histone deacetylases) that are involved in controlling the switch from open to closed chromatin. These complexes are all essential for life. We wish to understand the mechanisms through which these complexes recognise and manipulate chromatin. We will use Cryogenic Electron Microscopy to determine the three-dimensional structure of three important complexes bound to chromatin and gene-editing experiments to explore their function in cells. This research will lead to a fundamental understanding of the mechanisms by which these complexes regulate genes and may ultimately facilitate the development of novel therapeutics.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Specialization of chromosome segregation mechanisms in meiosis
Funder: Wellcome Trust

Abstract: Meiosis generates gametes with half the parental genome through two consecutive chromosome segregation events, meiosis I and meiosis II. Meiotic errors are prevalent in humans, accounting for frequent miscarriages, birth defects and infertility, yet the mechanistic origins of these errors are undefined. Our vision is to discover the molecular basis of the adaptations that sort chromosomes into gametes during meiosis. We will exploit the tractability of yeast meiosis to overcome the limitations of protracted meiosis and scarcity of material in other systems, to address three complementary aims. First, we will determine the mechanism by which kinetochores suppress crossover recombination near centromeres during meiotic prophase, and the significance of this suppression for chromosome segregation. Second, we will reveal how sister kinetochores are specifically fused, and the surveillance machinery re-wired, to permit sister chromatid co-segregation only during meiosis I. Third, we will identify the modified cell cycle controls that drive two consecutive chromosome segregation events during meiosis and determine how these controls couple chromosome morphogenesis to gametogenesis. The molecular pathways we discover will provide a framework for identifying potential sources of meiotic errors in humans.

Lay abstract: Sexual reproduction relies on the generation of eggs and sperm with half the DNA of the parent, through a form of cell division known as meiosis. Frequently, meiosis makes errors in dividing up the DNA so that more or less than half is put into the egg or sperm. When this happens, eggs and sperm fuse to create an embryo that has the wrong amount of DNA. Such embryos lack the correct “coding” to develop into a healthy baby, resulting in miscarriage, infertility and birth defects such as Downs syndrome. Our goal is to understand how molecules work together in meiosis to divide up the DNA. We will use yeast cells, which perform meiosis in a similar way to humans, as a discovery tool to unravel key processes. The findings will be an important step forward in identifying molecules that might function sub-optimally and cause infertility in humans.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Innovations Translational Partnership Award (Manchester)
Funder: Wellcome Trust

Abstract: The University of Manchester will use the three-year Wellcome Translational Partnership Award (TPA) renewal to build on the successful initiatives launched and delivered through the first TPA and continue to grow the translational research culture and develop the translational ecosystem in Manchester. The TPA funding will be used to address four aims: 1) support translational research; 2) connect across disciplines; 3) innovate with industry; and 4) change the culture by embedding translational research across the University. The Translational Research Facilitators will continue to bring together a network of support, facilities and expertise to build better links between science, technology and innovation, by removing barriers between disciplines to make the pathway to translation quicker and easier. The TPA will support translational research across all the stages of the translational pathway through pump-priming funding schemes, training (particularly informatics), symposiums and workshops, with a particular emphasis on new initiatives to support early career researchers. The Translation Manchester Research Network (TMRN), established under the initial TPA, brings together groups and organisations that exist to facilitate translational research across the One Manchester health innovation ecosystem, making it the ‘one-stop-shop’ for translational research support. The TMRN will continue to play a key role in the delivery of the initiatives set out in the TPA renewal. In addition, Innovation Labs will connect academics with industry partners, and pump-prime new collaborations and innovation through seed corn funding. The Research Connections Tool will enable researchers and clinicians to easily find appropriate collaborators across the University and our partner NHS trusts. To support delivery of these new initiatives a Translational Research Support Officer and a Translational Research Bioinformatician will be recruited into the Translation Manchester team.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE