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Recipients:
University of Cambridge

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The Cambridge History of Medicine 30 Sep 2020

This application is for support to develop a proposal for The Cambridge History of Medicine in six volumes. As General Editor, I will meet with a team of a dozen volume editors at a series of workshops to ask fundamental questions about what the history of medicine is, what it should be, and how best to represent it in these books.

Amount: £96,402
Funder: The Wellcome Trust
Recipient: University of Cambridge

A high-quality connectome of the complete adult Drosophila central nervous system 31 Mar 2020

Building on advances during our successful connectomics collaboration (2016-20), we now propose a very ambitious new goal: a complete, high-quality connectome for the male Drosophila central nervous system (CNS). With Wellcome support and leveraging Janelia’s unique electron microscopy imaging capability, we could turn image data into a fully analysed connectome. This would be the first CNS connectome of an animal with complex motor and cognitive behaviours. In contrast to existing fly datasets, it will be bilaterally complete, include brain and nerve cord and have intact sensory-motor connectivity. This connectome should have an enormous impact on the understanding of CNS-spanning circuitry underlying complex behaviour. We will publicly release initial draft and high-quality versions as soon as they are complete. We will immediately use it to study multisensory integration, memory recall, decision making, modification of brain states, the flexible organisation of motor behaviour, and sexually dimorphic circuits. It will provide a critical resource for > 200 labs worldwide studying Drosophila neurobiology (with impacts on developmental biology and molecular cell atlases) and provide new opportunities for theoretical neuroscientists to study complete, biologically-defined neural networks in a richly investigated organism. We expect general principles, applicable to all nervous systems, including those of humans, to emerge.

Amount: £4,119,965
Funder: The Wellcome Trust
Recipient: University of Cambridge

Targeting the gut in metabolic disease 31 Mar 2020

This project aims to identify new strategies to target the gut for the treatment of type 2 diabetes and obesity. Intestinal hormones regulate intestinal nutrient absorption, insulin secretion and appetite, and therapeutics based on the gut peptide GLP-1 are widely used for type 2 diabetes and obesity. Bariatric surgery causes weight loss and resolves diabetes at least in part via gut endocrine changes. This project will characterise human enteroendocrine cells using intestinal organoid cultures, building on our previous work using transgenic mouse models. To identify cells of interest, organoids will be engineered by CRISPR/Cas9 to express fluorescent sensors driven by hormonal promoters, allowing cellular analysis by transcriptomics, electrophysiology and real-time fluorescence imaging of e.g. Ca2+ and cAMP. We will characterize nutrient sensing pathways and identify receptors and signaling pathways potentially modifiable therapeutically. Using mouse and human tissues, we will identify circuitry involved in bidirectional cross-talk between gut endocrine cells and enteric/autonomic nerves. Building on our new methods to analyse peptides and the low molecular weight proteome by mass-spectrometry, we will investigate how plasma peptides respond to nutrient ingestion in health and metabolic diseases including diabetes, obesity, lipodystrophy and anorexia nervosa, and following bariatric surgery or dietary calorie restriction in obesity.

Amount: £2,381,203
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cellular dissection of Plasmodium falciparum erythrocyte invasion 31 Mar 2020

Plasmodium falciparum parasites still cause nearly half a million deaths each year. The repeated emergence of antimalarial drug resistance and the lack of a highly effective vaccine mean that there is an urgent need to identify new intervention targets. Erythrocyte invasion is an excellent target as it is essential for both parasite survival and for malaria pathology. Invasion involves multiple parasite ligands, but little is known about their function at the cellular level and even less about how they fit into the broader network of invasion proteins. This proposal will revolutionise our understanding of the function of two families of P. falciparum invasion ligands, the EBLs and the RHs, that are together responsible for the key decision point in the invasion process. The key goals are to: Systematically dissect functional equivalence between EBLs and RHs Establish the roles that EBLs and RHs play in discriminating between erythrocyte variants within and between humans Use innovative combinatorial approaches to move from a gene to a network understanding of EBL and RH function. The proposal will provide a step change for the field, both biologically and technically, and will identify new candidates for testing in a rationally designed, multi-component invasion-blocking vaccine.

Amount: £2,214,779
Funder: The Wellcome Trust
Recipient: University of Cambridge

Bridging the gap: biophysical models of human frontotemporal lobar degeneration 31 Mar 2020

To treat and prevent dementia in patients, it is essential to understand how microscopic changes in the human brain cause complex cognitive and behavioural disorders. My program addresses this critical gap in translational research, to facilitate clinical application of basic science discoveries. I have three goals, set in the context of frontotemproal dementia and progressive supranuclear palsy. First, I will develop quantitative biophysical models of human brain function that capture key cellular and pharmacological pathologies in vivo, with regional, laminar and synaptic specificity. These models of degenerating neuronal circuits are informed by individual measures of synaptic density (PET imaging with a SV2a ligand), GABA and glutamate (ultrahigh-field MR spectroscopy). They are optimised in vivo by inversion to magnetoencephalography, and tested post-mortem against neuropathology. This synergy of multi-modal imaging, together with Bayesian model comparison of Dynamic Casual Models, means one can drill down to the best mechanistic model of the human cognitive disorder. Second, I will show how harmful effects of dementia like apathy can be explained in terms of changes in synaptic density and loss of precision in hierarchical brain networks. Third, I will I demonstrate the readiness of my approach for experimental medicine, through longitudinal designs and pharmacological interventions.

Amount: £2,025,694
Funder: The Wellcome Trust
Recipient: University of Cambridge

Exploring mitochondrial metabolism in health and disease using targeted biological chemistry 31 Mar 2020

The molecular mechanisms by which mitochondrial reactive species, metabolites and redox signals contribute to physiology and pathology are unclear. This is in large part because these processes are difficult to assess and modulate in vivo. Our goals are to establish general chemical biology approaches to determine the mechanisms of mitochondrial physiology and dysfunction in vivo and from this develop new therapeutic strategies. The aims are based on the success of our previous Joint Investigator Award, but the specific chemical biology approaches to be used, the insights to be attained and the models have been refined and developed, based on our work over the past four years. These goals will be achieved by addressing three research challenges in cells and in vivo: A: Can we determine how mitochondria operate during normal physiology, and are disrupted during pathology, by targeting probes to measure reactive species and alterations to signaling pathways? B: Can targeting bioactive molecules to mitochondria prevent pathological disruption of mitochondrial function and generate potential therapies? C: Can the above methods to monitor and modulate mitochondrial function be assessed in animal models of human diseases and thus drive the development of rational, translatable therapies?

Amount: £875,659
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanisms and roles of transmissible RNA 04 Mar 2020

Protein coding and non-coding RNA can spread between cells and tissues of an organism. RNA mobility between organisms has been documented within and among different kingdoms of life including fungi, plants and animals. However, the underlying mechanisms and roles of such transmissible RNA are poorly understood. Our recent studies demonstrated that honeybees share biologically active RNA among members of the hive through secretion and ingestion of worker and royal jellies. The jellies harbor naturally occurring exogenous (e.g. viral) and endogenous RNA. These findings suggest that RNA transfer plays a role in social immunity and signaling between honeybees. Therefore, the key goals of this proposal are: to establish a metabolic RNA labeling system in honeybees; and to apply this system to study natural RNA transfer-mediated antiviral immunity and impacts on the physiology of recipient bees. To achieve these goals, I will combine RNA biology techniques and imaging with high-throughput sequencing to establish a functional transmissible RNA pathway in honeybees. This project will provide knowledge and tools that will enable studying the biology of RNA flow in other organisms, including humans, in diverse biological aspects; hence, will ultimately contribute to the development of RNA-based applications to promote health and disease control.

Amount: £1,393,480
Funder: The Wellcome Trust
Recipient: University of Cambridge

Open Access (COAF) Award 2019/20 30 Sep 2020

Not available

Amount: £1,029,579
Funder: The Wellcome Trust
Recipient: University of Cambridge

Cell-to-cell communication in the brain and tissue-specific phenotypes of mitochondrial disease 05 Dec 2019

Mitochondria are cellular organelles primarily involved in energy production. They are considered to be key to the function of eukaryotic cells. Nevertheless, mitochondrial diseases often only present in adulthood with tissue-specific symptoms. This means that cells and tissues must have coping strategies which temporarily maintain normal function when confronted with mitochondrial dysfunction. This proposal aims to test the hypothesis that cell-type composition and metabolic interactions between different cell types renders specific tissues more or less vulnerable to mitochondrial dysfunction. The neural stem cell (NSC) niche in the developing Drosophila brain is a powerful in vivo model for the microenvironment of neurons and NSCs in our human brain. I plan to study the in vivo metabolic requirements of Drosophila NSCs (Aim 1), and the metabolic and transcriptional response of surrounding niche cells upon mitochondrial dysfunction (Aim 2). In the last part of my proposal, I will investigate how metabolic regulation of the nuclear genome provide both a nuclear sensing mechanism and a buffer to tissue-wide mitochondrial dysfunction (Aim 3). Elucidating generic mechanisms of the tissue-wide response to mitochondrial dysfunction will lead to better insight into metabolic origins of neurodegenerative diseases and cancer and has the potential to uncover novel therapeutic approaches.

Amount: £1,268,713
Funder: The Wellcome Trust
Recipient: University of Cambridge

Primary Immunodeficiency: mechanism and diagnosis via integrative clinical immunogenomics. 03 Dec 2019

Primary Immunodeficiency (PID) has a devastating impact on the lives of patients and their families, and management is aided by genetic diagnosis. 80% of PID patients have no overt family history, and thus have been intractable to gene discovery. Our recent pilot study explored whole genome sequencing (WGS) to enhance diagnosis in PID, and found only 8% of such patients carried disease causing mutations in known PID genes. By applying new Bayesian analytical techniques, we identified multiple new PID-associated genes; causative deletions in regulatory regions; and interplay between novel high-penetrance monogenic and common variants, beginning to explain the variable penetrance of PID. We will expand this WGS PID cohort, already the world’s largest, and develop additional specialised statistical tools to incorporate deep clinical, immunophenotyping and antigen receptor repertoire data to enhance WGS analysis techniques. We will use genetic association data from immune-mediated diseases to increase power, and use genetic information to characterise the clinical features predictive of PID and enhance diagnosis. This collaborative effort will enhance understanding of PID biology, define phenotypic variability, discover new disease associated genes, increase diagnostic yield - but importantly develop mechanisms for WGS-based gene discovery in cohorts of sporadic patients, applicable beyond PID.

Amount: £4,041,766
Funder: The Wellcome Trust
Recipient: University of Cambridge

Elucidating the genetic and environmental determinants of congenital hypothyroidism 03 Dec 2019

I first identified mutations in the anion transporter SLC26A7 as a novel genetic cause of human and murine congenital hypothyroidism (CH), but its molecular role in thyroid hormonogenesis remains unclear. I will investigate SLC26A7 function in cultured primary thyrocytes, initially evaluating its role in pH regulation, seeking new insights into thyroid hormone biosynthesis. The incidence of CH with a normally-located gland-in-situ (GIS CH) is increasing, but its determinants are poorly defined. In a case-control study, I will investigate the roles of genetic variants, micronutrients (iodine, selenium, iron) and endocrine disruptors (perchlorate, thiocyanate and nitrate), in the pathogenesis of permanent and transient GIS CH. Confirmed involvement of environmental factors will have public health ramefications and mandate future trials of micronutrient supplementation for treatment or prevention of CH. The study will also provide insights into the aetiology of transient CH, a clinically important entity for which the cause is largely unknown. DUOX2/DUOXA2 mutations impair thyroidal H2O2 production, often causing transient CH. I will investigate whether maternal heterozygosity for DUOX2/DUOXA2 mutations in association with increased gestational demand for thyroid hormone biosynthesis, causes hypothyroidism during pregnancy. Gestational thyroid dysfunction would mandate future studies of childhood neurodevelopmental outcome and levothyroxine treatment in such patients.

Amount: £1,758,388
Funder: The Wellcome Trust
Recipient: University of Cambridge

How filopodia form 03 Dec 2019

Filopodia are finger-like actin rich projections from cells that are ubiquitously present during cell movement, are involved in cell connectivity, and are hijacked for internalization by pathogens. We established a cell-free system of filopodia-like structure formation using supported lipid bilayers and frog egg extracts, which has generated hypotheses about where and when filopodia form. My first aim is to discover how endocytosis and phosphoinositide lipid metabolism contribute to the time and place of filopodia formation and suppression in retinal ganglion cell neurons. We will examine the timing and contributions of neurotrophic factor signalling through PI(4,5)P2, PI(3,4,5)P3, PI(3,4)P2 and PI(3)P to membrane deformation and filopodial protrusion. We will explore filopodia in axon guidance, terminal arborization and synaptogenesis, and recovery from neuronal injury. My second aim is to identify the proteins needed for formation of filopodia-like structures to increase our understanding of the molecular mechanisms that determine filopodia function in cells. Where filopodia form determines the direction of cell movement, their length determines the extent of signal sensitivity and their lifetime determines the strength of signaling or duration of migration and adhesion. Our molecular and cellular studies may also give us information needed to manipulate actin regulation therapeutically.

Amount: £2,158,990
Funder: The Wellcome Trust
Recipient: University of Cambridge

Molecular mechanisms controlling peptide selection for immune recognition 03 Dec 2019

Peptide presentation on MHC-I molecules is central to mounting effective antiviral and antitumoral immune responses. However, we currently lack full insight regarding how peptides are selected onto these extremely polymorphic molecules. Following our discovery that TAPBPR is an MHC-I peptide editor which shapes the final antigen repertoire displayed for immune recognition, we have recently identified that polymorphism in MHC-I significantly impact on their ability to be edited by TAPBPR. Our findings question the concept that all MHC-I molecules undergo peptide selection via a largely identical manner. Our overarching aim is to gain insight into how polymorphisms in MHC-I influence the mechanism by which they gain peptide. We will focusing on three aspects: What impact do polymorphisms in MHC-I and TAPBPR have on the molecular mechanism of peptide selection? What is the specific biological function of TAPBPR? Can further molecular dissection of the presentation pathway reveal new insight into MHC-I biology and novel therapeutic targets? This work will enable deeper insight into how peptides are selected onto MHC-I. It will help uncover why specific MHC-I alleles are associated with particular disease. Furthermore, it will help in the development our novel TAPBPR-based therapeutics and maximise their full potential in cancer immunotherapy.

Amount: £1,947,412
Funder: The Wellcome Trust
Recipient: University of Cambridge

Tracing the dynamics of epithelial cell competition in normal and perturbed states 03 Dec 2019

The mechanisms that regulate cell fate promise fundamental insights into the pathways that promote tumour growth. Through advances in genetic lineage tracing and single-cell profiling, the functional identity, lineage relationships and fate behaviour of stem and progenitor cells have begun to resolve. Applied to epithelial tissues, these studies have challenged prevailing models, emphasizing the role of stochastic renewal programmes, fate priming and the flexibility of cell states during regeneration. Using a novel lineage tracing strategy based on variants of the multicolour Confetti reporter system, we will use quantitative modelling-based approaches to target the cellular and molecular mechanisms of epithelial cell fate, and how these programmes become subverted following the activation of oncogenic mutations. With a focus on columnar and squamous epithelia, where a foundational understanding of associated signalling pathways and transcriptional programmes is in place, we will define at clonal resolution the changes that take place in cell fate following the acquisition of oncogenic mutations, targeting tumour cells and the reaction of surrounding normal tissue – the tumour microenvironment. As prominent sites of disease, we will contrast tumour cell dynamics in the closed glandular arrangement of the intestinal epithelium and the open organization of the interfollicular skin epidermis and oesophagus.

Amount: £2,251,660
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanisms and Consequences of Inclusive Inheritance 03 Dec 2019

Heritability has traditionally been thought to be a unique feature of the genetic material of an organism, notably its DNA sequence. However, from studies of a variety of organisms, it is now clear that non-DNA sequence-based inheritance exists from microbes to mammals. The molecular mechanism(s) operating in humans remain opaque. However, understanding the impact of non-DNA sequence-based mechanisms is likely key to a full appreciation of heritability in health and disease. Here we will take ground-breaking steps towards understanding non-DNA sequence-based inheritance mechanisms and consequences. For this work we will focus on the imbred C. elegans model where we have the advantage of extensive genetic tools, a three day generation time and large numbers. In addition, we have identified the African Rift Lake cichlid radiation as a unique opportunity to dissect the contribution of epigenetics to plasticity, adaptation and heritability of phenotype in a vertebrate. While C. elegans gives us the ability to discover new mechanisms de novo we now also have developed paradigms to investigate the role of epigenetic inheritance on the plasticity and adaptivity in C. elegans and in cichlids. The latter is an important step towards a better understanding of inclusive inheritance in vertebrates more generally.

Amount: £2,475,352
Funder: The Wellcome Trust
Recipient: University of Cambridge

Biogenesis and bioengineering of human platelets 03 Dec 2019

Platelets are essential for haemostasis and play critical roles in innate immunity, angiogenesis and tissue repair. They are derived from megakaryocytes, each of which generates several thousand platelets. A major goal is to generate platelets in vitro, to address shortage of platelet supply for transfusion, and to enable fundamental discovery of gene function. To date, however, only very small numbers (approximately 10 per megakaryocyte) of platelets can be made in vitro. We propose a step change using novel in vitrosystems, to increase generation efficiency by 1-2 orders of magnitude. We will use two in vitrosystems (mouse lung vasculature and microcirculation microfluidics) using forward-programmed iPSC-derived megakaryocytes. Our new data show that passage of megakaryocytes through lung vasculature ‘educates’ them to undergo a sequence of changes: reversible deformation, enucleation and abscission to release platelets. We aim to understand the detailed biology of these processes using CRISPR-edited megakaryocytes. We also show we can make human platelets in our novel microfluidic system and will optimize this to bioengineer large quantities of cells, by learning from the biology of the ex vivolung preparation. This is potentially transformative for fundamental understanding of human platelets and megakaryocytes, and for their bioengineering for clinical uses.

Amount: £593,451
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of glycosphingolipids in modulating membrane protein trafficking 03 Dec 2019

Glycosphingolipids (GSLs) are specialised lipids enriched in the outer leaflet of the plasma membrane (PM) and defects in GSL metabolism underlie a range of devastating diseases. I have shown for the first time a direct link between GSL metabolic defects and changes in the abundance of disease-associated PM proteins. Changes to the cell surface abundance of these proteins are driven by trafficking defects and gene expression changes: pathways that may be mechanistically linked. My preliminary work highlights that the role of GSLs in membrane trafficking has been under-appreciated. I now seek to define the molecular mechanisms that link GSL abundance to disease pathways: how do specific GSL-protein interactions direct membrane trafficking; and what are the consequences of this mistrafficking? We will target specific enzymes in GSL metabolic pathways, monitor lipid and protein changes using quantitative mass spectrometry and visualise co-ordinated protein trafficking from the endoplasmic reticulum using an innovative fluorescence-based secretory assay. Using high-resolution structural techniques we will determine how the specificity of GSL-protein interactions is defined and exploit these insights to feedback into our cell-based assays. My research proposal implements a multidisciplinary strategy that will reveal crucial new insights into how this important class of lipids influence cell fate.

Amount: £1,902,595
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding and disrupting the link between obesity and metabolic disease 03 Dec 2019

Obesity is strongly associated with common metabolic diseases (T2DM, fatty liver and cardiovascular disease) which collectively account for a huge global health burden. Insulin resistance underpins this association and our goal is to understand, and reverse, its molecular pathogenesis. Having worked on rare monogenic lipodystrophies, almost all of which are associated with the metabolic diseases typically seen in obesity, for ~20 years, we have recently convincingly shown that subtle forms of lipodystrophy are a major factor in common insulin resistance/metabolic disease. Specifically we showed that SNPs associated primarily with reduced hip (femorogluteal) fat, are as strongly associated with T2DM and cardiovascular disease risk as variants associated with central adiposity. We will build on this step-change in understanding by: Deepening understanding of the molecular mechanisms by which adipocytes form and then store surplus energy in unilocular lipid droplets Performing an experimental medicine intervention study designed to demonstrate the clinical and molecular impact of alleviating energetic overload using a very low energy diet in patients with partial lipodystrophy. Investigating the source and action of two hormones (GDF15 and FGF21) which we hypothesize to be stress signals released in response to sustained overnutrition. Both of these molecules represent exciting therapeutic opportunities.

Amount: £1,944,579
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding the role of ionocytes in a cystic fibrosis (CF) context using human induced pluripotent stem cell (hiPSC)-derived airway epithelial cells (AECs). 06 Nov 2019

Cystic Fibrosis (CF) affects over 10000 people in the UK. It is a recessive monogenic disease caused by a double mutation in the gene encoding for CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) and it affects multiple tissues, especially the lung. There is still no cure for this disease and patients require life-long treatment and eventually lung transplantation. This projects aims to study a newly discovered cell type in the human airway epithelium. These cells have been called pulmonary ionocytes because of their ion-exchange function and their similarity to ionocytes in Xenopus and zebrafish. Because they express high levels of CFTR, they have been proposed to have a key role in CF. I will derive airway epithelial cells, including ionocytes, from iPSCs from healthy and CF patients. I will do an extensive characterisation of the cells and I will study their role in the healthy and diseased epithelium using approaches such as single cell RNA-seq and assessment of cilia dynamics and mucus clearance. Overall, this project will shed light into the role of pulmonary ionocytes in the epithelium and into the pathophysiology of CF. This will lead to the identification of potential therapeutic targets and future treatments for the disease.

Amount: £300,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Biomolecular condensation of hairpin proteins coordinates cytoplasmic clients to spatially distinct microdomains of the ER membrane 06 Nov 2019

The endoplasmic reticulum (ER), as a single continuous membrane network, coordinates a variety of biological processes across the entire cell, providing a platform for the spatiotemporal segregation of cytoplasmic biochemistry – a crucial feature for cell survival. Despite this, our understanding of how the ER corrals most cytoplasmic clients to specific sites on its membrane remains slim. ER structure is partially governed by a series of hairpin proteins known to stabilise specific membrane curvatures. The Reticulons (RTNs) and Receptor Expression-Enhancing Proteins (REEPs) are two such families of protein. We have shown that RTN/REEPs cluster into ER microdomains and contain cytosolic-facing intrinsically disordered regions which enable the formation of biomolecular condensates, potentially tethering specific cytosolic proteins to the ER membrane. Thus, we propose the novel and testable hypothesis that membrane curvature-stabilising RTN/REEPs drive regional functional specificities at ER microdomains. To test this, we will generate a comprehensive spatial map of RTN/REEP-microdomains using single-molecule localisation microscopy, with a custom optical-tweezer configuration used to quantify precise membrane curvature preferences for each hairpin. Using two orthogonal screens we aim to identify a complement of cytosolic proteins capable of co-condensing with each RTN/REEP, performing appropriate bioassays to assess the functional consequences of destabilising hairpin:cytoplasmic-partner interactions.

Amount: £300,000
Funder: The Wellcome Trust
Recipient: University of Cambridge