NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Systems Neuroscience of Primate Social Cognition
Funder: Medical Research Council

Abstract: Primate social cognition involves sophisticated decision-making, observational learning and perspective-taking. To study the underlying neuronal mechanisms, we combine multi-area multi-electrode electrophysiological recordings with reversible interventions and computational modelling while monkeys perform well-established decision tasks in a social context. In a value-guided decision task, two monkeys observe and learn from each other's choices how to obtain subjectively preferred rewards. In a social rule-based decision task, two monkeys observe and learn from each other which of several abstract rules is currently valid and leads to reward. Neuronal recordings in both tasks allow us to identify neuronal signals related to shared, task-general social processes (self-other distinction, observational learning, social choice prediction, perspective-taking) and task-specific signals (subjective valuation and reward processing vs. rule following and conflict processing). We use chronic electrode arrays and semi-chronic multi-electrode drives to target areas previously implicated in social behaviour, including anterior cingulate cortex, amygdala and connected temporal-lobe areas, and prefrontal areas implicated in decision-making and advanced cognition, including frontal pole and dorsolateral prefrontal cortex. Using electrical microstimulation and reversible pharmacological interventions, we disrupt local activities and network interactions before and during task performance to establish which of these brain areas make essential contributions to social task performance. We integrate the neural and behavioural data using biophysically realistic neural-network modelling to build task-specific and task-general computational models, and thereby uncover the mechanisms and circuit architectures underlying primate social cognition.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health Categories: NEUROLOGICAL
Award Title: Systems approach to therapeutic combinations for glioblastoma: new targets and agents delivered and sequenced for synergy
Funder: Cancer Research UK

Abstract: Glioblastoma (GBM) is a dismal disease whose treatment is limited by drug resistance and likely by the blood-brain barrier (BBB). Here we will identify new evidence-led combination therapies and enhance their delivery to GBM cells in vivo, so as to improve patient outcomes. We will address how rewiring of cellular signaling pathways promotes therapeutic resistance, including to standard-of-care therapies. We will combine our complimentary expertise to develop a unique drug-combination discovery and delivery platform, specifically tailored to GBM. We propose a multidisciplinary approach to address 7 key aims:-

AIms
Aim1: Identification and validation of novel therapeutic targets and agents in combination with standard-of-care radiotherapy and temozolomide.
Aim2: Target validation and drug resistance modelling in vivo. 
Aim3: Pathway profiling following target perturbation.
Aim4: Development and application of an interactive computational modelling platform for predicting novel drug combinations and biomarkers in GBM.
Aim5: Biological validation and prioritization of drug-target combinations.
Aim6: Optimization of functionalized layer-by-layer nanoparticles (LbL NP) for enhanced delivery of novel combination therapies across the BBB.
Aim7: In vivo proof-of-concept in animal models of GBM.

Methods:
We have assembled an international team of leaders in the following: high-content phenotypic screening optimized for target validation and drug combination testing across 2D and 3D human GBM assays; patient-derived cellular and mouse models of GBM combined with non-invasive intravital imaging and immune profiling; protein-level pathway analyses, computational modeling and systems biology to predict changes across cellular signaling networks in response to treatment; and nanoscale material science that has huge potential for targeting multiple agents across the BBB to GBM cells in their microenvironment. Through co-development of state-of-the-art methodologies in an integrated platform, we will establish a novel drug-target combination discovery and delivery platform to develop new therapies for GBM in a rapid translational pathway, with clinical advice at each stage.

How the results of the research will be used
This project represents a balance of new screening and integrated systems-level approaches to inform new therapeutics and the testing of existing exemplar high-value combination hypotheses that our work has already identified. The results will be exhaustively tested pre-clinically and thereafter compiled into de-risked and prioritised combinations, with mechanism of action/biomarker packages, that can be tested clinically with UK partners. Our team offers new approaches that will be co-developed and aid the wider GBM research community, advancing the field’s understanding of current treatment failures in GBM.


Research Activity Codes: 5.1 PHARMACEUTICALS
Health Categories: CANCER AND NEOPLASMS
Award Title: Systems neuroscience of human long-term memory, ageing and dementia
Funder: Medical Research Council

Abstract: Memory problems are some of the first complaints as we grow older, and can be particularly debilitating following brain injury or neurodegenerative disease. This programme investigates human long-term memory and its disorders using novel psychological tasks, combined with neuroimaging and neuropsychological assessment of patients, in addition to computational modelling, multivariate analyses of large cohorts and advanced methods development. Understanding the neurological bases of memory is vital for developing treatments, and pertinent to the MRC 2019 Delivery Plan priorities of “prevention and early detection”, in terms of promoting healthy ageing and detecting early signs of Alzheimer’s Disease.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: MENTAL HEALTH;NEUROLOGICAL
Award Title: T Cell Responder
Funder: Innovate UK

Abstract: * Protective immunity to SARS-CoV-2, like other viruses, depends on a combined immune response by specific antibodies and T lymphocytes. As we race to immunise the world and end the pandemic, there is considerable unmet need for better, high-throughput immune monitoring. In diverse settings, from healthcare and public health planning to travel and hospitality, there is demand to know if people are carrying immunity. These answers also impact if and when people will require vaccine boosters. While the increased momentum behind antibody testing has supplied finely-tuned, cost-effective, reliable tests, T lymphocyte assays remain cumbersome, costly and limited to specialist labs. The team at Imperial College are leaders in T lymphocyte immunology and have, since the start of the pandemic, been at the forefront of characterising immunity to the virus. However, the assays involve complex cell separations and equipment. We have invested considerable effort in defining which aspects of immunity are truly specific to SARS-CoV-2 and not the result of cross-reactivity with the related common cold viruses. Recent work has been devoted to reimagining T lymphocyte assays to consider what it would take to demonstrate, rapidly, that a small blood sample contains specific cells responding to the virus - that is, who can be defined as having immune memory for this virus - 'a T cell responder'. We have been able to show novel biomarkers of the response, measurable in immune people in a matter of hours. During this project we plan to refine our observations to the extent of producing a pilot point-of-care test that can be developed as a test of T lymphocyte immunity. We envisage utilisation in many settings: international immunity certificates, management of optimal vaccine schedules in at-risk patient groups, public health decisions on when to boost vaccines. Once optimised, the approach can easily be extended to other settings, from immunity to other pathogens, to monitoring of the anti-tumour response in cancer patients given immunotherapy. For these reasons, we have given the project and proposed kit an easy and self-explanatory name - 'T Cell Responder'.


Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Award Title: TDP-43 Misregulation in neurodegeneration
Funder: Wellcome Trust

Abstract: TDP-43 is a conserved RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 normally autoregulates its expression by binding to the 3’UTR of its cognate transcript. We have linked disrupted TDP-43 autoregulation to disease, showing that disease-linked TDP-43 missense mutations disturb TDP-43 autoregulation causing a gain of function, finding that ALS patients harbour non-coding variants in the 5’ and 3’UTRs of TDP-43 that could disturb TDP-43 expression and observing that TDP-43 misregulation in mice causes selective brain atrophy reminiscent of human ALS-FTD. We will follow these leads to understand the causes and consequences of TDP-43 misregulation and elucidate therapeutic targets and biomarkers for ALS-FTD. Specifically, we will dissect the TDP-43 autoregulation protein interactome in wild-type and TDP-43 missense mutant cells by performing in-cell protein-RNA interaction studies and native mass spectrometry. To determine the significance of ALS-linked UTR variants in regulating TDP-43 expression we will perform an in-vitro CRISPR/Cas9 mutagenesis screen with parallel genomic and transcriptomic sequencing. To understand how TDP-43 misregulation causes regional and cell type-specific neurodegeneration we will use in situ sequencing of mouse brain sections to obtain transcriptomic information with single cell resolution.

Lay Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating brain diseases linked to disturbances in the protein TDP-43. TDP-43 tightly autoregulates its expression, but disease-linked mutant TDP-43 escapes this process leading to increased TDP-43 and regional brain atrophy in mice reminiscent of human ALS-FTD. Additionally, ALS patients harbour uncharacterised non-coding mutations in the UTRs of TDP-43, which could directly disturb autoregulation. We will use RNA-protein interaction assays and proteomics to characterise the network of proteins involved in TDP-43 autoregulation. We will recreate UTR variants in human cells using CRISPR and determine their effect on TDP-43 expression and neuronal viability. Finally, we will examine the brain transcriptome in situ in TDP-43 mutant mice to elucidate mechanisms underlying regional brain vulnerability in ALS-FTD. These studies will identify how TDP-43 expression is regulated in health and disease and determine how this ubiquitously expressed protein causes selective vulnerability in the brain.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL
Award Title: TRPA1; a potential therapeutic target in idiopathic pulmonary fibrosis
Funder: Medical Research Council

Abstract: General protocols: Primary human lung myofibroblasts (HLMFs) are grown from the lung parenchyma of patients with IPF and healthy non-fibrotic control (NFC) tissue removed at lung resection. AIM 1:  The expression of TRPA1 in HLMFs and human lung parenchymal tissue from non-fibrotic control (NFC) and IPF donors TRPA1 expression will be examined in NFC- and IPF-derived HLMFs both at rest and following activation with TGFb1 and H2O2 activation. We will examine mRNA expression (qRT-PCR), protein expression (western blotting), functional expression (patch clamp electrophysiology), tissue expression (immunohistochemistry).  AIM 2: The functional role of TRPA1 in HLMF pro-fibrotic activity We will study the effect of TRPA1 blockers/RNA silencing on HLMF function proliferation, wound healing, soluble collagen secretion, aSMA expression/stress fibre formation, and contractility in collagen gels. AIM 3: The mechanistic interactions between ROS, TGFb1, and TRPA1 signalling in HLMFs We will use ratiometric Ca2+ imaging and fluorescent probes to detect intracellular Ca2+ and ROS in HLMFs activated with H202 and TGFb1 +/- TRPA1 antagonists/siRNA. Inhibitors of ROS and NOX4 will be used to investigate ROS-dependency. We will also assess TGFb1-dependent pro-fibrotic signalling (SMAD2/3 phosphorylation and nuclear translocation, phosphorylation of P38 MAPK/JNK) in the presence of ROS inhibitors and TRPA1 antagonists/siRNA.  AIM 4: The contribution of TRPA1 to TGFb1-dependent fibrogenesis in a human lung parenchymal tissue ex-vivo model of fibrosis We will study TRPA1 antagonists, anti-oxidants and NOX4 inhibitors in our human lung parenchymal model of lung fibrogenesis, using qRT-PCR profiling arrays and immunohistochemistry. This human lung parenchymal assay avoids the important tissue-dependent heterogeneity applicable to TRPA1 pharmacology, and offers the opportunity to benchmark the potential clinical effectiveness of TRPA1 antagonists against pirfenidone.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: RESPIRATORY
Award Title: Targeting New Mechanisms In The Control Of Thymus Function To Restore Balanced T-cell Production
Funder: Medical Research Council

Abstract: This proposal continues towards our long-term goal of dissecting mechanisms of thymus function that will inform future therapies to restore and replace defective immunity. To examine the role of thymic epithelial cells (TEC) in T-cell development, we have generated novel TEC reporter tools to dissect poorly understood pathways in TEC development that will lead to a better understanding of how epithelial thymic microenvironments develop and function. Building on our novel observation that eosinophils are essential for thymus regeneration, we will identify mechanisms controlling endogenous recovery of thymus function that following insult, including ablative therapy. We will also examine thymus reconstitution following bone marrow transplant, and identify mechanisms that limit the recovery of self-tolerant T-cell production. Finally, we will develop an in-depth definition of conventional and Foxp3+ regulatory Recent Thymus Emigrants (RTE), to provide accurate qualitative and quantitative measurement of thymus function. By defining mechanisms of thymus function and identifying processes that influence the recovery of thymus function, our findings will be important to inform future strategies that aim to improve thymus-dependent immune reconstitution. Our specific goals are: 1. Use newly produced RANKVenus/CCL21Tomato TEC reporter mice to define developmental pathways controlling the formation of functionally distinct medullary TEC subsets that relate to distinct functions of the thymus medulla. 2. Examine mechanisms that control endogenous thymus recovery following ablative therapy, by focussing on a proposed tuft cell/ILC2/eosinophil axis for thymus regeneration. 3. Identify mechanisms that limit the recovery of self-tolerant T-cell production following bone marrow transplantation. 4. Define a molecular signature for mouse and human conventional and Foxp3+ Regulatory RTE, to enable accurate analysis of how therapeutic interventions impact thymus function.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Targeting torpor circuits across species: towards translation
Funder: Medical Research Council

Abstract: We are interested in torpor as a model of resilience that might be mimicked in an ICU setting. Several lines of evidence recently identified neurons in the preoptic area (POA) of the mouse hypothalamus that are active during torpor, and whose reactivation induces hypothermia and inactivity. This evidence suggests a role for a glutamatergic Adcyap1-expressing projection from the POA to the dorsomedial hypothalamus (DMH). It is not clear whether POA-Adcyap1 neurons generate all the physiological adaptations associated with torpor. We will address this question in mice using a genetic activity dependent TRAP2 strategy to express DREADDs or opsins in POA neurons that are active during torpor (i.e., TRAPed). We will assess in vivo and in the working heart brainstem preparation whether this POA ensemble generates a typical profile of cardiorespiratory, thermal, and metabolic depression. We will compare activating all POA neurons that were TRAPed during torpor with the effects of activating a specific subset of POA Adcyap1-expressing neurons using an Adcyap1-Cre mouse line. Both these will be compared with natural torpor in wild type mice.  Rats do not enter torpor, however chemo-activating excitatory neurons in the POA of the rat induces a hypothermic state with reduced oxygen consumption and bradycardia ('synthetic torpor'). We will investigate the degree to which synthetic torpor in the rat recapitulates natural torpor in the mouse, whether synthetic torpor is driven by a glutamatergic projection from the POA to the DMH, and explore the natural drivers for this population of neurons in the rat.  We will test whether synthetic torpor is protective in a lung-injury model in the rat, with a 2x2 factorial design with measures of physiological parameters (e.g. SpO2, respiratory rate), lung histology/weights, inflammatory markers, and lactate. This work will inform the approach to be taken towards developing synthetic torpor as a possible therapeutic strategy.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL;RESPIRATORY
Award Title: Technical feasibility for the Revive + Adrenaline Auto-injector
Funder: Innovate UK

Abstract: An adrenaline auto-injector (AAI) is prescribed to people who are susceptible to severe allergies that put them at risk of anaphylaxis -- a life threatening allergic reaction. Despite medical advice to carry the injector on person at all times, our user studies show:



1. People do not carry them nearly as much as they should

2. Not receiving adrenaline for an anaphylactic reaction is the biggest common factor in fatalities as adrenaline is the only drug known to prevent death due to anaphylaxis.



Revive is a new AAI concept developed as a graduation project at the Royal College of Art (RCA). This project seeks to extend the promising results of this prior phase wherein a proof of concept(PoC) was developed. Designed with the patient at its centre, it's much smaller size makes it easy to carry and its form makes it discreetly fit within a patient's life. These combine like never before to counteract the identified problems of being too large to practically carry continuously and adverse impacts on quality of life from an obvious medical form and associated stigma. Revive achieves this through a fresh examination of how a syringe should be designed for an AAI. The proprietary needle injection system concept has been awarded InnovationRCA's support and is patent pending in the UK.



We have developed a PoC where we tested functionality and medicine dosage. Revive also has simplified instructions designed to improve accurate use. Revive, unlike most current offerings in the market, incorporates a variety of needle lengths.



Now, the team seeks to extend this achievement by conducting a technical feasibility study through the engineering audit of the concept.


Research Activity Codes: 5.3 MEDICAL DEVICES
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM
Award Title: Telomeric chromatin and VSG allelic exclusion in African trypanosomes
Funder: Wellcome Trust

Abstract: Trypanosomes are single-celled parasites that causes lethal diseases in humans and livestock. The parasite is covered in variable surface glycoprotein (VSG) that enables host immune system evasion. VSG is often swapped by ‘antigen switching’, which is central for the parasite’s virulence.My group found that the active VSG suppresses expression of other VSGs. As VSG genes are located near the ends of chromosomes, we hypothesise that the characteristic and highly repetitive sequences at chromosome ends are important for suppression. To facilitate studying this, I will manipulate the dosage of these sequences using new genome editing tools (CRISPR/Cas9).Also, I will explore the function of the proteins that package these regions. Again, I will use CRISPR/Cas9 to create parasites with a single copy of each gene encoding these packaging proteins, allowing me to manipulate those genes as well. These proteins impact DNA repair, DNA replication and gene regulation.This project will provide new insight into how chromosome ‘caps’ function, how VSG genes behave at these locations and may also reveal potential drug targets.


Research Activity Codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION
Award Title: Thailand Africa and Asia Programme - PPE Award
Funder: Wellcome Trust

Abstract: The Wellcome Thailand AAP has conducted high quality impactful research for 40 years on infectious diseases of major public health concern, leading to the widespread adoption of new approaches and treatments for many of them including malaria, melioidosis, and rickettsial infections. In our fifth decade we will focus on ensuring sustainable impact and influence on policymakers by strengthening our research network and developing the capabilities of our partner institutions. Our vision is to:
 
1. Through research continue to address public health problems with regional and global relevance, using cutting edge approaches to seek affordable and deployable solutions to disease prevention, diagnosis and patient management.
 
2. Maximise our public health research’s uptake and impact, incorporating health economics analysis and goal-driven engagement with policymakers, national academic institutions, hospitals, industry partners, communities and the general public.
 
3. Work with our local host institutions to increase their national and global impact by integrating activities including training programmes, joint research projects, and supporting partner-led programmes to translate research into policy and practice.
 
Our goal is to improve life quality and expectancy by reducing the adverse impact of infectious diseases, which account for much of the disparity in health metrics between low and high income countries.


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