NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Investigating the metastatic microenvironment in pancreatic cancer
Funder: Cancer Research UK

Abstract: Background:
 Pancreatic ductal adenocarcinoma (PDAC) is a devastating metastatic disease for which better therapies are urgently needed. We recently found that PDAC liver metastasis critically depends on the early recruitment of metastasis associated macrophages (MAMs) to the liver, resulting in the transactivation of resident hepatic stellate cells into myofibroblasts (mFbs) and the formation of a growth promoting metastatic niche. Our recent findings suggest that MAMs and mFbs also suppress cytotoxic T cell functions at the metastatic site, thereby allowing disseminated cancer cells to escape immune surveillance. Our data suggest that MAMs and mFbs play a key role in PDAC metastasis and may serve as potential therapeutic targets for PDAC liver metastasis. However, the molecular mechanisms needed to form a hospitable metastatic niche remain poorly understood.

 Aims:
 Our overall objective is to gain a better understanding of how MAMs and mFbs affect anti-tumour immunity at the metastatic site of PDAC, in order to develop more effective therapeutic approaches for metastatic pancreatic cancer patients.

The specific objectives are:
1. To understand the role of macrophage-derived granulin in T cell infiltration at the metastatic site.
2. To identify MAM and mFb immunosuppressive factors that inhibit cytotoxic T cell functions in metastatic PDAC.
3. To test, in pre-clinical PDAC metastasis mouse models, whether genetic and pharmacological blockade of granulin, and the newly identified immunosuppressive regulators, restores anti-tumour immunity.

Methods:
 - Molecular tools and genetic mouse models to study the role of macrophage-derived granulin in T cell exclusion in metastatic PDAC.
- Flow and mass cytometry analysis to understand the effect of granulin on immune cell infiltrates at the metastatic site.
 - RNA-Seq and bioinformatic analysis to identify characteristic immunosuppressive transcriptional profiles of MAMs and mFbs derived from mouse and human PDAC liver metastases.
- In vitro primary cell co-culture models to assess the molecular mechanisms by which MAMs and mFbs suppress T cell functions.
- Pre-clinical imaging to understand the effect of MAMs and mFbs immunosuppressive functions in metastatic PDAC mouse models.
- Fresh and archived liver biopsies from metastatic PDAC patients to validate our findings obtained from pre-clinical animal models.

How the result of the research will be used:
In this proposal we aim to understand the mechanisms by which MAMs and mFbs impair anti-tumour immunity in order to develop more effective combination therapies for metastatic pancreatic cancer, a disease with unmet clinical needs.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS
Award Title: Investigating the molecular mechanisms of intracellular bidirectional cargo transport
Funder: Wellcome Trust

Abstract: Intracellular trafficking pathways depend on the opposing microtubule-based motors kinesin and dynein. Both types of motor can simultaneously bind the same cargo for bidirectional transport on microtubules. Kinesin and dynein bind to many of the same cargo adaptors (e.g. BICD-family). However, it is unclear how opposite-polarity motors are linked to the same vesicle and how adaptors regulate directional switches in the cell. My research goal is to use post-Golgi Rab6-vesicles to investigate how bidirectional transport is coordinated. Mechanistic insight into this process is necessary to understand how cells correctly distribute cargo to maintain their function. I will first structurally characterise how purified Rab6 recruits motors and adaptors. I will subsequently reconstitute bidirectional motility of Rab6-liposomes in vitro with purified proteins. With this tool, I will explore how combining different motors and BICD adaptors alters motile behaviour using single-molecule total internal reflection microscopy. To address how motors are organised during bidirectional transport, I will determine the architecture of a multi-motor Rab6-liposome complex on microtubules using cryo-electron microscopy and tomography. Structural observations will be validated using site-directed mutagenesis and imaging of Rab6-vesicles in cells using lattice light-sheet microscopy. Together, this will provide extensive structural and functional information about dynamic bidirectional transport mechanisms.

Lay Abstract: Cells require accurate transport of organelles and vesicles to maintain their proper function. Transport of cellular cargo is mainly carried out by molecular motors kinesin and dynein. These motors walk on microtubules, which act as polarised tracks to allow trafficking in the cell. Kinesin and dynein move in opposite directions on microtubules yet can bind to the same cargo. This leads to back-and-forth movement of cargo (bidirectional transport) but the regulation of directional switches is unclear. My goal is to understand how kinesin and dynein activities are coordinated on bidirectional vesicles. To this end, I will primarily use protein biochemistry, electron microscopy and fluorescence-based microscopy techniques to investigate the structure and dynamics of bidirectional vesicles. Together, this will provide a mechanistic insight into what happens to the kinesins when dynein is active (or vice versa) and how distribution of cargo is regulated to ensure a cell's function is maintained.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE;NEUROLOGICAL
Award Title: Investigating the physiological DNA replication initiation reaction
Funder: Wellcome Trust

Abstract: In all cells chromosome replication requires key initiator proteins to unwind the DNA at specific sites termed origins. Despite the fundamental importance of DNA replication initiation, crucial aspects of the process remain poorly understood.
 
 
 
My vision is to identify all essential features of both the bacterial replication origin and DNA replication initiation proteins in vivo. This comprehensive reverse genetic analysis will guide biochemical investigations into the activities associated with deleterious mutations, thereby revealing the interactions and steps necessary for the physiological initiation reaction.
 
 
 
Towards this goal I have created a bespoke tool: an inducible heterologous replication initiation system that allows construction and characterization of mutations within endogenous replication initiation factors. This methodology, combined with assays we developed to analyze DNA replication initiation in vitro, led us to identify a new essential bacterial replication origin element (Richardson et al. Nature 2016). We will build upon this successful approach and go on to develop more sophisticated heterologous replication systems, opening the door to studying all aspects of chromosome replication.
 
 
 
Importantly, the bacterial DNA replication machinery is an underexploited drug target. Knowledge of bacterial DNA replication resulting from this work will provide a guide for disrupting this process in pathogenic species.

Lay Abstract: In all organisms genome duplication is required for cell proliferation. This essential process involves the concerted activity of several multiprotein complexes to replicate an exact copy of the DNA.
 
The bacterial DNA replication machinery is significantly simpler than the related eukaryotic system, making it well-suited for detailed analysis. Additionally, the bacterial DNA replication machinery is an attractive drug target, and new antibiotics are urgently needed to combat drug-resistant strains.
 
In all cells chromosome replication requires key initiator proteins to unwind the DNA at specific sites termed origins. Despite the fundamental importance of DNA replication initiation, crucial aspects of the process remain poorly understood. This knowledge-gap is a result of DNA replication being an essential activity required for cell viability.
 
To circumvent this challenge I have developed new tools that allow the normally essential DNA replication initiation factors to be either removed or mutated. This opens the possibility of determining all of the sites within both the chromosome origin and the initiation proteins required for DNA replication initiation. My long-term goal is to expand this toolkit and investigate the entire DNA replication machinery.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION
Award Title: Investigating the role of lung Tissue resident memory T-cell in the immunopathology of human TB
Funder: Wellcome Trust

Abstract: This proposal will examine the involvement of lung Tissue resident memory (Trm) T-cells in the human immune response to TB. Using unique access to fresh human lung tissue, we find evidence of non-recirculating T-cells, consistent with a Trm subset. The importance of Trm to pathogen immunity is becoming increasingly apparent and limited data from mice indicates they are highly active against TB. However, nothing is known about their role in humans and this is important because, as Trm do not recirculate, they are missing from TB immunology data generated to date, which comes from blood. Even bronchioalveolar lavage does not accurately describe the Trm response. We know T-cells are crucial for immunity to TB, and our failure to establish T-cell correlates of protection may come from not taking Trm into account. We will use novel tools, including single cell sequencing, Mass Cytometry and multiparimeter fluorescence microscopy to investigate the role of Trm in the TB response in human lung. Then, using a novel 3D-granuloma model we will test this observational data to determine the functional details of protective or harmful T-cell responses. This will establish the T-cell correlates of protection in humans and provide a basis for rational vaccine design.

Lay Abstract: TB remains the leading cause of death from infectious disease globally, and an improved vaccine is desperately needed. Unfortunately, the most recent attempt to do so failed. The truth behind this failure is that, as a field, we still do not understand the immune correlates of protection and therefore, vaccine development remains a shot in the dark. TB is primarily a disease of the lung, and yet immune correlates of protection in humans have been exclusively studied the blood. There is a growing understanding that blood and tissue are not the same; and that many immune cells, once in tissue, do not in fact recirculate. This proposal seeks to address this problem by studying TB immunity in human lung tissue. This will revolutionise our understanding of human TB immunology and represents the best chance of discovering the immune correlates of protection, from which an improved TB vaccine can be developed.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Award Title: Investigating the roles of transcription factor eomesodermin in the establishment and maintenance of the trophoblast lineage in the early mouse embryo
Funder: Wellcome Trust

Abstract: The placenta is an organ crucial in supporting the development of mammalian embryos. The cells that ultimately produce the placenta (“trophectoderm” or “trophoblast” cells) produce important signals to pattern the developing embryo, and the placenta itself is instrumental in transporting nutrients to, and waste products away from, the embryo. Eomesodermin (eomes) is a protein essential in the specification and maintainance of trophoblast cells, and the trophoblast stem cells that can be derived from the embryo. However, its mechanism of action hasn't been investigated in depth. Therefore, in this project, we will "tag" the eomes protein, allowing us to isolate it from the cell, and observe what regions of the DNA it binds to, what genes it thus activates, and which proteins it interacts with. Once we identify potential “target” genes of eomes, we will delete them from trophoblast stem cells, as well as from embryos themselves, to see what the effects are on the development and maintenance of trophoblast cells and the placenta. This will help dissect the function of eomes and its target genes in the placenta and embryonic development. This, in turn, can also give us insight into placental defect-associated diseases in human embryonic development.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE;REPRODUCTIVE HEALTH AND CHILDBIRTH
Award Title: Investigating whether Human Embryonic stem cell derived Neuromesodermal progenitors require positional identity to produce spatially restricted progeny.
Funder: Wellcome Trust

Abstract: The neuromesodermal progenitors (NMPs) are a group of cells found in the developing embryo, which form the spinal cord and surrounding muscle.  NMPs are present at the tail end of the embryo, first producing the head, then trunk and finally the tail end, changing the genes they express as they do this. A subset of these time-regulated genes includes the HOX genes, named HOX1-HOX13. At early stages, NMPs poised to make the neck express HOX1, while successively later NMPs that make the trunk and tail progressively express more of the genes until HOX13 is expressed in tail tip.  Studies removing these genes showed that each one is necessary to make vertebrae of a particular identity.  It is unknown whether the expression of HOX genes in NMPs at different times during development is important to set identity.
It is currently only possible to make NMPs in culture with neck and upper trunk identity.  Therefore, I hope to develop a method to make human NMPs which express all the Hox codes.  Once we have done this, we will research what is controlling how the cells gain Hox identity.  Finally, I will research if HOX code controls NMP differentiation when placed into embryos.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Investigation of base and prime editing to correct COL7A1 mutations and development of organoid model for RDEB
Funder: Wellcome Trust

Abstract: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a severe skin disease with no cure. Normally, two layer of the skin are held together by rope like structures called anchoring fibrils, which are made of Type VII Collagen (C7). However, in patients with RDEB the anchoring fibrils don’t work and the layers of the skin are fragile, resulting in blistering, chronic wounds, and cancer. RDEB is caused by mutations in the gene COL7A1, which makes C7. I aim to correct those COL7A1 mutations with new gene editing tools called base editor and prime editor, to fix the anchoring fibrils in patient cells. After editing COL7A1, I will use molecular techniques including Sanger sequencing, qPCR, western blot and immunofluorescent microscopy to confirm if the edit worked and if it fixed C7 function. It’s also important to know whether the gene editors have affected areas of the DNA which I don't want to edit, so I will do “off-target analysis” to test the safety of these tools. Additionally, I aim to make 3D models of "RDEB skin in a dish" to aid future research. By the end of my PhD I aim to have aided the development of potential cures for RDEB.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: SKIN;GENERIC HEALTH RELEVANCE
Award Title: Kinase-phosphatase coupling at the kinetochore and the maintenance of chromosomal stability
Funder: Cancer Research UK

Abstract: Background
We have recently identified a feedback network that integrates the activities of the two main kinases (Aurora-B/MPS1) with the two main phosphatases (PP1/PP2A-B56) that act at the kinetochore. These are the principle regulators of the spindle assembly checkpoint (SAC) and kinetochore-microtubule attachments, and therefore they are the cells primary defence against cell division errors and aneuploidy. The vast majority of cancers fail to segregate their genome correctly, leading to chromosomal instability (CIN) and accelerated tumour evolution, and I predict that defects in this feedback network could be responsible.

 The principle is that the network itself, rather than the individual components, imparts key properties such as robustness and reliability to the chromosome segregation process. These properties are likely to be weakened in cells with CIN, to allow the type of subtle errors needed for tumours to propagate viable levels of aneuploidy. It is therefore critical that we understand how the whole network functions together within the context of cancer.

I will tackle this problem using an interdisciplinary mix of quantitative cell biology, computational modelling and molecular biology to characterise the network in a range of cells with and without CIN. In parallel, I will draw on the power of synthetic biology and gene-editing to; 1) determine the full mechanistic details of the network, 2) uncouple it to determine how it best safeguards cell division, and 3) manipulate it to examine the effect on CIN.

Aims
(1) To determine the mechanistic details of the feedback network
(2) To understand how the network regulates the SAC
(3) To understand how the network regulates kinetochore-microtubule attachments.
(4) To investigate if perturbations to the feedback network cause CIN.

Methods
The proposal relies on the fact that all aspects of the feedback network can be quantified accurately, and manipulated efficiently, in human cells. I have established a number of different methods to achieve this, including a novel chemical-genetic system to inducibly relocalise endogenous phosphatases with small molecule drugs. This is the first time phosphatases have been manipulated in this way and I will exploit this technology throughout this proposal.

How the results of this research will be used
These studies will reveal how kinases and phosphatases work together to safeguard cell division and how this could be perturbed to cause CIN. Collectively, this may provide new opportunities for cancer treatment by identifying network weaknesses that could be exploited therapeutically to target cancer cells with CIN.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Award Title: LMICSS - AAP Malawi
Funder: Wellcome Trust

Abstract: LSTM is submitting an application for salary supplements in connection with two roles at MLW:   • Director of MLW  • Deputy Director Total Number of Current Applications in progress for LMICSS from LSTM for all programmes:   1 Total Number of Current Applications in process for LMICSS to be held at MLW:  1 (comprising 2 nominees)


Research Activity Codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES)
Health Categories: INFECTION
Award Title: Learn to Discover (L2D): A Training Platform in Data Sciences and Machine Learning for Biomedicine and Health Researchers.
Funder: Medical Research Council

Abstract: In bio and health sciences data complexity and volume is now outstripping the compute-intensive physical sciences. Challenges of massive datasets, needs for real-time predictive modelling and computer execution of human intelligence-level tasks are growing rapidly.  To address this, research and education leaders in the applications of data science and quantitative approaches to bio-, biomedical and health research will build on an outstanding track record to create a data science, ML and AI e-learning and training platform called Learn 2 Discover (L2D) to meet the needs of their wider peer community. L2D will develop specific, highly relevant skills for participant's immediate needs. Insights into the data challenge of other fields will narrow persistent knowledge gaps - for example, through L2D, drug developers might encounter more data aware clinicians and conversely laboratory scientists might appreciate the priorities of health practitioners and what data is gatherable. L2D will deliver: a) Core skills in data handling, supervised and unsupervised ML, working with complex, high dimensional data. ("live" within 4 months of start-up) b) A portfolio of "use case" scenarios e.g. image analysis, digital pathology, neuroscience, drug development, molecular structure-function, genotype-phenotype relationships, synbio, cancer diagnostics and functional genomics using validated real-world data  c) Insight into advances in AI and Deep Learning e.g. various neural networks, reinforcement learning, autoencoders and natural language processing and more d) Good practice in computing and data handling to address the reproducibility crisis  e) Web publishing for sharing predictors and code f) Accessing cloud computing to spin-up flexible resource for large compute problems  g) Collaborative coding and project workshops with skilled tutors  h) Support materials and coaching for "local" trainers in universities and businesses to facilitate the uptake and adoption.


Research Activity Codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY);8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Learning as Bayesian inference.
Funder: Wellcome Trust

Abstract: For biological organisms, learning involves changing synaptic weights -- that is, changing the connection strengths among neurons -- with the goal of setting the weights to values that ensure the animal functions as effectively as possible. This, however, is hard: information is noisy and often ambiguous, and must be used to set over 100 trillion weights. To understand how animals do this, we treat learning as a probabilistic inference problem: given sensory information, the goal is to compute a probability distribution over weights, not just point estimates, as is commonly believed. This leads to learning rules that contain a feature not found in any other proposed learning rules: the more uncertain a neuron is about the weight of a synapse, the more plastic that synapse is. This makes intuitive sense: if the uncertainty about a weight is large, new information should strongly influence its value, while if the uncertainty is small, little learning is needed. It also allows synapses to efficiently use incoming information, greatly improving learning. Finally, it allows organisms to match learning rates to incoming information -- speeding up learning when the rate of new information is high, and slowing it down when the rate is low.


Research Activity Codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Learning to care in unprecedented times: the impact of COVID-19 on nursing education
Funder: The British Academy

Abstract: Even before the COVID-19 outbreak, there was a crisis in the healthcare workforce, with 40,000 unfilled nursing vacancies. This case study of a group of final year pre-registration nursing students aims to assess the impact of the COVID-19 pandemic on this group in the midst of the emergency and the immediate aftermath, and the wider repercussions for nursing education. It will explore the students’ experiences of the pandemic and inform any immediate support they may require. The project will document the short-term graduate outcomes for this cohort and their ‘imagined futures’, exploring the role of class, gender and ‘race’ in shaping their educational trajectories. In doing so it will offer vital sociological insights into the impact of the pandemic on nursing education, the support that this cohort and future nursing students may require, and the implications for addressing the workforce shortage.


Research Activity Codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION